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  • CLASSES

    Heparins For Flushing
    Unfractionated Heparins

    DEA CLASS

    Rx

    DESCRIPTION

    A glycosaminoglycan anticoagulant; its molecular weight ranges from 5,000-30,000 daltons; derived from porcine or bovine tissue; produces a less predictable anticoagulant response than LMWH; used to prevent and treat DVT and PE, to treat unstable angina or myocardial infarction.

    COMMON BRAND NAMES

    Hep-Lock, Hep-Lock U/P, Hepflush-10, Monoject Prefill Advanced Heparin Lock Flush, SASH Normal Saline and Heparin

    HOW SUPPLIED

    Heparin Sodium (Porcine)/Heparin Sodium (Porcine), Dextrose/Heparin Sodium (Porcine), Sodium Chloride/Heparin Sodium (Porcine);Sodium Chloride/Hepflush-10/Hep-Lock/Hep-Lock U/P/Monoject Prefill Advanced Heparin Lock Flush/SASH Normal Saline and Heparin Intravenous Inj Sol: 0.5mL, 1mL, 2U, 10U, 100U, 1000U, 2000U, 2500U, 5000U, 10000U, 20000U, 100-0.45%, 100-0.9%, 100-5%, 2-0.9%, 40-5%, 50-0.45%, 50-5%
    Heparin Sodium (Porcine)/Hepflush-10/Hep-Lock/Hep-Lock U/P/Monoject Prefill Advanced Heparin Lock Flush Subcutaneous Inj Sol: 0.5mL, 1mL, 10U, 1000U, 5000U, 10000U, 20000U

    DOSAGE & INDICATIONS

    For the treatment of deep venous thrombosis (DVT) or pulmonary embolism; for the treatment of arterial thromboembolism including cerebral thromboembolism; or for the treatment of mural thrombosis.
    Intravenous Infusion dosage (weight-based)
    Adults

    80 units/kg IV bolus, then maintenance infusion of 18 units/kg/hour IV continuous infusion. If the aPTT is less than 35 (1.2 times normal), increase infusion rate by 4 units/kg/hour and rebolus with 80 units/kg IV. If aPTT is 35 to 45 (1.2 to 1.5 times normal), increase infusion rate by 2 units/kg/hour and rebolus with 40 units/kg IV. If aPTT is 46 to 70 (1.5 to 2.3 times normal), maintain infusion. If aPTT is 71 to 90 (2.3 to 3 times normal), decrease infusion rate by 2 units/kg/hour. If aPTT is more than 90 (more than 3 times normal), hold infusion for 1 hour and decrease rate by 3 units/kg/hour. Repeat aPTT every 6 hours for the first 24 hours, then every morning, unless it is outside the therapeutic range. Patients should be treated for 5 days or more and oral anticoagulation should be overlapped for 4 to 5 days or more. Heparin can be discontinued on day 5 to 6 if the INR has been within the therapeutic range for 2 consecutive days. Patients with massive PE or severe iliofemoral thrombosis should be offered a longer period of heparin therapy (about 10 days).

    Pregnant females

    Full dose heparin as a continuous IV infusion should be given for 5 to 10 days, followed by full dose heparin subcutaneously until term. Subcutaneous heparin should be given every 12 hours and adjusted to prolong the aPTT into the therapeutic range. Heparin should be discontinued 24 hours for average risk recurrence of DVT or 4 to 6 hours for patients at high risk for recurrence (e.g., proximal DVT within less than 2 weeks) before elective induction of labor.

    Children and Adolescents

    75 to 100 units/kg IV load then 20 units/kg/hour IV as an initial maintenance dose. Adjust dose to maintain aPTT 60 to 85 seconds, assuming this reflects an antifactor Xa level of 0.3 to 0.7 units/mL.

    Neonates and Infants

    75 to 100 units/kg IV load then 28 units/kg/hour IV as an initial maintenance dose. Adjust dose to maintain aPTT 60 to 85 seconds, assuming this reflects an antifactor Xa level of 0.3 to 0.7 units/mL.

    Intermittent Intravenous dosage
    Adults

    5,000 to 10,000 units IV every 4 to 6 hours or 100 units/kg IV every 4 hours. Dosage should be adjusted according to coagulation test results.

    Infants, Children, and Adolescents

    Initially, 50 units/kg IV as a loading dose then 100 units/kg IV every 4 hours. Adjust dosage according to aPTT results. Continuous infusion is preferred over intermittent administration in pediatric patients.

    Subcutaneous dosage
    Adults

    8,000 to 10,000 units subcutaneous every 8 hours or 15,000 to 20,000 units subcutaneous every 12 hours.

    For thrombosis prophylaxis.
    For thrombosis prophylaxis, including arterial thromboembolism prophylaxis, during extracorporeal circulation in patients undergoing open heart or other cardiovascular surgery.
    Intravenous dosage
    Adults

    Initially, at least 150 units/kg IV. For procedures expected to last less than 60 minutes, doses up to 300 units/kg IV may be used. For procedures expected to last longer than 60 minutes, doses up to 400 units/kg IV may be used. Further dosage should be based on coagulation test results (e.g., activated clotting time (ACT)).

    For coronary artery thrombosis prophylaxis during percutaneous coronary intervention (PCI) in patients not receiving abciximab therapy.
    Intravenous dosage
    Adults

    60 to 100 units/kg IV bolus; maintain the activated clotting time (ACT) within 250 to 300 seconds by the HemoTec device or 300 to 350 seconds by the Hemochron device. Postprocedural heparin is not routinely given for uncomplicated PCI. Early femoral sheath removal is recommended (e.g., when the ACT falls to less than 150 to 180 seconds) to reduce access site complications.

    Adolescents, Children, Infants, and Neonates

    100 units/kg IV bolus is recommended for pediatric patients requiring cardiac catheterization via an artery. For prolonged procedures, further doses may be necessary; however, specific recommendations are not available.

    For deep venous thrombosis (DVT) prophylaxis.
    Subcutaneous dosage
    General medical patients with risk factors for DVT (e.g., cancer, bed rest, heart failure, severe lung disease)

    5,000 units subcutaneously every 8 to 12 hours, however, some clinicians use 7,500 units subcutaneously every 12 hours or LMWH.

    Moderate risk adults undergoing surgery (e.g., minor procedure, with additional risk factors; non-major surgery for patients 40—60 years with no risk factors; major surgery in patients younger than 40 years with no risk factors

    5,000 units subcutaneously every 8 to 12 hours, starting 1 to 2 hours before surgery, LMWH, intermittent pneumatic compression, or elastic stockings.

    Higher risk adults or geriatric undergoing surgery (e.g., non-major surgery in patients > 60 years or with additional risk factors; major surgery in patients older than 40 years or with additional risk factors)

    5,000 units subcutaneously every 8 hours, LMWH, or intermittent pneumatic compression (IPC). In all higher-risk general surgery patients, the use of mechanical prophylaxis with elastic stockings (ES) or IPC is recommended initially. In very high-risk general surgery patients with multiple risk factors, combination of pharmacologic (i.e., heparin or LMWH) and mechanical (i.e., ES or IPC) prophylaxis is recommended.

    Female adults undergoing major gynecologic surgery for benign disease, no additional risk factors

    5,000 units subcutaneous every 12 hours, starting 1 to 2 hours prior to surgery.

    Female adults undergoing extensive gynecological surgery for malignancy

    5,000 units subcutaneously every 8 hours, starting 1 to 2 hours prior to surgery.

    Adults undergoing major open urologic procedure (including high-risk)

    5,000 units subcutaneously every 8 to 12 hours, starting 1 to 2 hours prior to surgery, LMWH, elastic stockings (ES), or intermittent pneumatic compression (IPC). For patients at highest risk, heparin 5,000 units subcutaneously every 8 to 12 hours in combination with ES with or without IPC.

    Adults undergoing elective hip replacement surgery

    5,000 units subcutaneously every 8 to 12 hours, starting 1 to 2 hours before surgery, as an alternative for LMWH. Treatment should continue for a minimum of 10 to 14 days after surgery; up to 35 days is recommended. The use of an intermittent pneumatic compression device (IPCD) during the hospital stay is encouraged.

    Adults undergoing hip-fracture surgery

    5,000 units subcutaneously every 8 to 12 hours, starting 1 to 2 hours before surgery, as an alternative to LMWH. Treatment should continue for a minimum of 10 to 14 days after surgery; up to 35 days is recommended. The use of an intermittent pneumatic compression device (IPCD) during the hospital stay is encouraged.

    Adults undergoing neurosurgery

    5,000 units subcutaneously every 8 to 12 hours, starting 1 to 2 hours before surgery, as an alternative to elastic stockings (ES) or intermittent pneumatic compression (IPC) alone; however, use must be balanced with the clinically important risk of intracranial bleeding. Low-dose heparin may be offered in combination with ES or IPC for patients at high-risk and may be more effective than either modality alone.

    Adults with acute myocardial infarction

    7,500 units subcutaneously every 12 hours until fully ambulatory for all patients not receiving heparin for another reason.

    Adults with acute ischemic stroke and impaired mobility

    5,000 units subcutaneously every 8 to 12 hours, LMWH, or a heparinoid, if not contraindicated. Low-dose heparin should be restricted for 24 hours after thrombolytic administration. Low-dose heparin may be used safely in combination with aspirin. For patient with contraindications to anticoagulant therapy, intermittent pneumatic compression devices or elastic stockings are recommended.

    For mural thrombosis prophylaxis in patients with an acute transmural anterior myocardial infarction.
    Subcutaneous dosage
    Adults

    12,500 units subcutaneously every 12 hours for 10 days after an acute anterior MI. When compared to 5,000 units subcutaneously every 12 hours, left ventricular mural thrombosis was observed less frequently in the high-dose heparin group. There was no difference in the frequency of hemorrhagic complications between the 2 groups.

    For arterial thromboembolism prophylaxis in patients with prosthetic heart valves.
    Intravenous or Subcutaneous dosage
    Adults

    80 units/kg IV bolus, then initial maintenance infusion of 18 units/kg/hour IV continuous infusion or 17,500 to 20,000 units subcutaneously every 12 hours, adjusted to prolong the aPTT 1.5 to 2 times control. Heparin (or LMWH) should be given initially with oral anticoagulants until the INR is within the therapeutic range for 2 consecutive days.

    Pregnant females

    Adjust doses of heparin subcutaneously every 12 hours throughout pregnancy to maintain a mid-interval aPTT at 2 times control or more or anti-Xa level maintained at 0.35 to 0.7 units/mL. Or, at the 13th week of pregnancy, change to warfarin until the middle of the third trimester then restart heparin or LMWH until delivery. Long-term anticoagulation should resume postpartum.

    For thrombosis prophylaxis and/or for pulmonary embolism prophylaxis in patients at increased risk after sustaining an acute MI (e.g., Q-wave infarction, severe LV dysfunction, CHF, history of systemic or pulmonary embolism, 2D echo evidence of mural thrombus, or atrial fibrillation).
    Intravenous or Subcutaneous dosage
    Adults

    In patients not receiving thrombolytic therapy, 75 units/kg IV bolus, followed by 1,250 units/hour IV, with a target aPTT of 1.5 to 2 times control (also see dosage for treatment of an evolving acute MI). For patients who have received heparin following thrombolytic therapy (see acute myocardial infarction indication for initial heparin dosage recommendations following thrombolytic therapy), continue IV heparin or change to subcutaneous heparin (initial dose about 17,500 units every 12 hours) beyond 48 hours to maintain the aPTT 1.5 to 2 times control, LMWH, or convert to oral anticoagulation.

    For thrombosis prophylaxis, including arterial thromboembolism prophylaxis, during hemodialysis.
    Intravenous dosage
    Adults

    2,000 to 5,000 units IV bolus at the initiation of dialysis, followed by 10 to 20 units/kg/hour IV infusion directly into the arterial port of the dialysis circuit or repeated bolus doses as needed to maintain the activated clotting time (ACT) or whole blood partial thromboplastin time (WBPTT) at about 150% of baseline. The extent of anticoagulation is based on risk factors for bleeding and co-existing conditions. In patients at moderate risk for bleeding, administration of lower loading doses and lower maintenance infusion rates can be used to maintain the ACT or WBPTT at about 115% to 125% of baseline.

    For coronary artery thrombosis prophylaxis during percutaneous coronary intervention (PCI) in patients receiving abciximab concomitantly.
    Intravenous dosage
    Adults

    50 to 70 units/kg IV bolus; maintain the activated clotting time (ACT) at 200 seconds or more with either the HemoTec or Hemochron device. Remove femoral sheaths after the procedure when the ACT falls to less than 150 to 180 seconds.

    For deep venous thrombosis (DVT) prophylaxis in pregnant females.
    Subcutaneous dosage
    Pregnant females with a history of DVT with a transient risk factor; no current risk factors

    Surveillance and post partum anticoagulation.

    Pregnant females with an episode of idiopathic DVT; thrombophilia (confirmed laboratory abnormality); no current long-term anticoagulation

    Options include surveillance, heparin 5,000 units subcutaneously every 12 hours, adjusted dose heparin subcutaneously every 12 hours to maintain a target anti-Xa level of 0.1 to 0.3 units/mL, or LMWH with postpartum anticoagulation.

    Pregnant females, no prior DVT; thrombophilia (confirmed laboratory abnormality); no current long-term anticoagulation

    Options include surveillance, heparin 5,000 units subcutaneously every 12 hours, or LMWH with postpartum anticoagulation. Indication for active prophylaxis is strongest in antithrombin-deficient women.

    Pregnant females with 2 or more episodes of DVT, and/or long-term anticoagulation (e.g., single episode of DVT, idiopathic or associated with thrombophilia)

    Options include adjusted dose heparin subcutaneously every 12 hours to maintain a target anti-Xa level of 0.1 to 0.3 units/mL or LMWH with postpartum, long-term anticoagulation.

    Pregnant females with mechanical heart valves

    Adjusted doses of heparin subcutaneously every 12 hours throughout pregnancy to maintain a mid-interval aPTT at 2 times control or more or anti-Xa concentration maintained at 0.35 to 0.7 units/mL. Or, at the 13th week of pregnancy, change to warfarin until the middle of the third trimester then restart heparin or LMWH until delivery. Long-term anticoagulation should resume postpartum.

    For intravascular catheter occlusion prophylaxis.
    NOTE: The amount of heparin solution in each single dose is sufficient to prevent clotting within the lumen of the indwelling catheter for up to 24 hours. If the catheter is used for withdrawal of repeated blood samples for laboratory tests and the presence of heparin is likely to interfere with the test, the in situ heparin flush should be cleared from the catheter by aspirating and discarding a volume of solution equivalent to that of the indwelling catheter before the desired blood sample is drawn. If the drug to be administered is incompatible with heparin, the entire catheter or lumen should be flushed with sterile water or normal saline before and after the medication is administered. Following the second flush, the heparin flush solution may be reinstilled into the set.
    To maintain patency of single and multiple-lumen catheters.
    Intravenous catheter
    Adults

    Use heparin 100 units/mL. Instill enough volume to fill the lumen of the catheter (usually 2 to 5 mL) to the tip. Catheters should be flushed daily, with additional flushes given when stagnant blood is observed in the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.

    Infants, Children, and Adolescents weighing more than 10 kg

    In general, heparin 100 units/mL is used for pediatric patients weighing more than 10 kg. Instill enough volume to fill the lumen of the catheter. Catheters should be flushed at least daily; certain types of catheters are more prone to clotting and require more frequent flushing. Refer to site-specific guidelines for details. Additional flushes should be administered when stagnant blood is observed in the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.

    Infants and Children weighing less than 10 kg

    In general, heparin 10 units/mL is used for infants and small children (e.g., weight less than 10 kg). Instill enough volume to fill the lumen of the catheter. Catheters should be flushed at least daily; certain types of catheters are more prone to clotting and require more frequent flushing. Refer to site-specific guidelines for details. Additional flushes should be administered when stagnant blood is observed in the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.

    Neonates†

    0.5 units/kg/hour IV infused through the line is recommended for maintaining central venous access line patency in neonates. Use only preservative free solutions.

    To maintain patency of peripheral catheters (i.e., heparin locks).
    Intravenous catheter
    Adults

    Use heparin 100 units/mL. Instill enough volume to fill the lumen of the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.

    Infants, Children, and Adolescents weighing more than 10 kg

    In general, heparin 100 units/mL is used for pediatric patients weighing more than 10 kg. Instill enough volume to fill the lumen of the catheter. Catheters should be flushed at least daily; certain types of catheters are more prone to clotting and require more frequent flushing. Refer to site-specific guidelines for details. Additional flushes should be administered when stagnant blood is observed in the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.

    Infants and Children weighing less than 10 kg

    In general, heparin 10 units/mL is used for infants and small children (e.g., weight less than 10 kg). Instill enough volume to fill the lumen of the catheter. Catheters should be flushed at least daily; certain types of catheters are more prone to clotting and require more frequent flushing. Refer to site-specific guidelines for details. Additional flushes should be administered when stagnant blood is observed in the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.

    Neonates†

    0.5 units/kg/hour IV infused through the line is recommended for maintaining central venous access line patency in neonates. Use only preservative free solutions.

    To maintain patency of arterial lines.
    Intraarterial catheter
    Adults

    Use a final heparin concentration of 1 unit/mL (range: 0.5 to 2 units/mL). In order to avoid large total doses and systemic effects, use 0.5 units/mL in patients receiving multiple lines containing heparin.

    Infants, Children, and Adolescents

    Use a final heparin concentration of 0.5 units/mL to run at 1 mL/hour IV.

    Neonates

    Use a final heparin concentration of 0.5 units/mL running at a rate of 1 mL/hour IV for peripheral arterial catheters. A final heparin concentration of 0.25 to 1 unit/mL with a total heparin dose of 25 to 200 units/kg/day IV is recommended to maintain patency of umbilical artery catheters (UAC). Use only preservative free solutions.

    To maintain line patency in patients receiving total parenteral nutrition (TPN).
    TPN solution additive
    Adults, Adolescents, and Children

    A final heparin concentration of 1 unit/mL may be added to TPN solutions intended for central or peripheral administration.

    Neonates and Infants

    A final concentration of heparin of 0.5 to 1 unit/mL added to peripheral or central TPN solutions. Lower concentrations may be used in small infants receiving larger TPN volumes to avoid systemic heparin effects.

    For the prevention of pregnancy loss and/or thrombosis in patients with antiphospholipid antibody syndrome (APLA).
    In pregnant women with APLA and >= 2 early pregnancy losses, or >= 1 late pregnancy loss, or preeclampsia, or intrauterine growth restriction (IUGR), or abruption.
    Subcutaneous dosage
    Adult females

    Antepartum aspirin and heparin 5000 Units subcutaneous every 12 hours or adjusted doses of heparin subcutaneous every 12 hours to maintain a anti-Xa level of 0.1—0.3 Units/mL, or LMWH.

    In pregnant women with thrombophilic defects and recurrent miscarriages; a miscarriage during or after the second trimester; or preeclampsia, intrauterine growth restriction (IUGR), or abruption.
    Subcutaneous dosage
    Adult females

    Consider low-dose aspirin with either heparin 5000 Units subcutaneous every 12 hours or adjusted doses of heparin subcutaneous every 12 hours to maintain a anti-Xa level of 0.1—0.3 Units/mL, or LMWH. Give anticoagulants postpartum.

    In pregnant women with APLA and a history of venous thrombosis, with current long-term anticoagulation.
    Subcutaneous dosage
    Adult females

    Adjusted doses of heparin subcutaneous every 12 hours to maintain a anti-Xa level of 0.1—0.3 Units/mL or LMWH. Give anticoagulants postpartum. Resume long-term oral anticoagulation therapy postpartum.

    In women with antiphospholipid antibodies and no previous venous thrombosis and no pregnancy losses.
    Subcutaneous dosage
    Adult females

    Options include surveillance, heparin 5000 Units subcutaneous every 12 hours, prophylactic LMWH, or low-dose aspirin.

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

    The use and the dosing of heparin in the management of DIC are controversial. For selected patients (i.e., those with clinically overt thromboembolism or extensive deposition of fibrin), low doses of heparin 300 to 1,000 units/hour or 15 units/kg/hour IV infusion have shown some benefit. Patients with antithrombin III levels less than 25% may not respond to heparin. In general, heparin should be continued until fibrinogen levels are more than 100 mg/dL and platelet counts are more than 100,000/mm3.

    Children and Adolescents

    75 to 100 units/kg IV load then 20 units/kg/hour IV as an initial maintenance dose. Adjust dose to maintain aPTT 60 to 85 seconds, assuming this reflects an antifactor Xa level of 0.3 to 0.7 units/mL.

    Neonates and Infants

    75 to 100 units/kg IV load then 28 units/kg/hour IV as an initial maintenance dose. Adjust dose to maintain aPTT 60 to 85 seconds, assuming this reflects an antifactor Xa level of 0.3 to 0.7 units/mL.

    For the treatment of unstable angina.
    NOTE: In 2009, the USP adopted new reference standards and manufacturing controls for heparin that result in a 10% reduction in the potency. This change in heparin potency may have clinical significance in situations that require dosage adjustments and more frequent monitoring, especially when aggressive anticoagulation is needed, including pediatric patients undergoing extracorporeal membrane oxygenation, adults and children undergoing cardiopulmonary bypass, and the treatment or prevention of life-threatening thromboses. Healthcare providers should exercise clinical judgement when deciding what dose to administer and continue to individualize heparin dosing. Higher doses may be required to achieve and maintain the desired anticoagulant effect in some patients.
    Intravenous dosage
    Adults

    The American College of Chest Physicians (ACCP) recommends that all patients hospitalized for the treatment of unstable angina receive aspirin PO and heparin 75 Units/kg IV bolus, followed by an initial maintenance dose of 1250 Units/hour IV, with a target of prolonging the aPTT to 1.5—2 times control. Heparin therapy should be maintained for at least 48 hours, or until the unstable pattern resolves. Clinical practice guidelines for the diagnosis and management of unstable angina recommend maintaining an aPTT of 1.5—2.5 times control. An initial IV infusion of 15—18 Units/kg/hour has also been recommended.

    For the treatment of an evolving acute myocardial infarction (AMI) (i.e., coronary artery thrombosis†) in patients who have received thrombolytic therapy with alteplase (tPA), reteplase (r-PA), or tenecteplase (TNK-tPA)..
    NOTE: In 2009, the USP adopted new reference standards and manufacturing controls for heparin that result in a 10% reduction in the potency. This change in heparin potency may have clinical significance in situations that require dosage adjustments and more frequent monitoring, especially when aggressive anticoagulation is needed, including pediatric patients undergoing extracorporeal membrane oxygenation, adults and children undergoing cardiopulmonary bypass, and the treatment or prevention of life-threatening thromboses. Healthcare providers should exercise clinical judgement when deciding what dose to administer and continue to individualize heparin dosing. Higher doses may be required to achieve and maintain the desired anticoagulant effect in some patients.
    For patients receiving streptokinase or anistreplase (APSAC) concurrently.
    Intravenous dosage
    Adults

    If streptokinase (SK) or anistreplase (APSAC) is used, heparin should be given only in those patients who are at high risk for systemic emboli (e.g. large anterior MI, atrial fibrillation, previous embolus, or known LV thrombus) (See standard dosage). Heparin should not be given <= 4 hours after fibrinolytic therapy and should be given when the aPTT is < 70 (goal aPTT 50—70 seconds). After 48 hours, consideration may be given to subcutaneous heparin administration (initial dose about 17,500 Units every 12 hours to maintain aPTT 1.5—2 times control), LMWH, or oral anticoagulants. If the patient has no risk factors and SK or APSAC is the thrombolytic that was used, therapeutic heparin is not recommended.

    Subcutaneous dosage (streptokinase only)
    Adults

    12,000 Units subcutaneous every 12 hours for at least 48 hours. Heparin should not be given <= 4 hours after fibrinolytic therapy and should be given when the aPTT is < 70 (goal aPTT 50—70 seconds).

    Intravenous dosage
    Adults

    60 Units/kg IV bolus (Max: 4000 Units) given simultaneously with initial dose of thrombolytic therapy followed by heparin 12 Units/kg/hour IV (Max: 1000 Units/hour) adjusted to keep the aPTT at 1.5—2 times control (50—70 seconds) for 48 hours. All AMI patients without contraindications and who are not receiving heparin for another reason should receive not less than low-dose heparin (7500 Units subcutaneous every 12 hours) or LMWH until ambulation to prevent venous thrombosis. Heparin therapy should be maintained for longer than 48 hours only in patients with a high risk of systemic or venous thromboembolism (e.g., anterior MI, CHF, previous embolus, atrial fibrillation).

    MAXIMUM DOSAGE

    NOTE: Since heparin-induced bleeding has been related to dose in addition to other patient specific factors, it would seem to be prudent to limit the dose of heparin, especially in high-risk patients.

    Adults

    Maintain the aPTT below levels that correlate with heparin concentrations of 0.4 units/mL (by protamine titration) or an anti-factor Xa concentration of 0.7 units/mL.

    Geriatric

    Maintain the aPTT below levels that correlate with heparin concentrations of 0.4 units/mL (by protamine titration) or an anti-factor Xa concentration of 0.7 units/mL.

    Adolescents

    Maintain the aPTT below levels that correlate with heparin concentrations of 0.4 units/mL (by protamine titration) or an anti-factor Xa concentration of 0.7 units/mL.

    Children

    Maintain the aPTT below levels that correlate with heparin concentrations of 0.4 units/mL (by protamine titration) or an anti-factor Xa concentration of 0.7 units/mL.

    Infants

    Maintain the aPTT below levels that correlate with heparin concentrations of 0.4 units/mL (by protamine titration) or an anti-factor Xa concentration of 0.7 units/mL.

    Neonates

    Maintain the aPTT below levels that correlate with heparin concentrations of 0.4 units/mL (by protamine titration) or an anti-factor Xa concentration of 0.7 units/mL.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    It appears that hepatic impairment does not affect the elimination of heparin; however, patients with hepatic disease may have increased risk of bleeding during heparin therapy.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Use extreme caution during the preparation, dispensing, and administration of any heparin-containing products for pediatric patients. Heparin injection is available in various concentrations, and the inadvertent administration of the incorrect concentration could result in devastating consequences. Fatal hemorrhages have occurred in pediatric patients (including neonates) due to medication errors in which concentrated 1 mL heparin injection vials were administered rather than 1 mL 'catheter lock flush' vials.
    Administer intravenously or subcutaneously. Intramuscular injection can produce large hematomas caused by accidental puncture of veins and, therefore, should be avoided. There is evidence that administration by intermittent IV injection is associated with more bleeding than when administered by continuous infusion. Therefore, if administered intravenously, a continuous infusion is preferred.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Intermittent IV injection:
    Administer IV either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection.
     
    Continuous IV infusion:
    Dilute desired dose in a prescribed amount of 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer's Injection. Invert container at least 6 times after diluting to ensure adequate mixing. Periodically mix during the infusion.
    Administer IV bolus doses over 10 minutes in pediatric patients.
    Infuse intravenously via an electronic infusion pump. Adjust rate based on aPTT or plasma heparin concentration (by protamine titration or anti-factor Xa assay).

    Subcutaneous Administration

    Using a 25 to 27 gauge needle that is 3/8 to 5/8 inches in length, inject by deep subcutaneous injection into the lower abdomen; do not aspirate or massage injection site. Take care not to inject intradermally. Rotate injection sites frequently.
    The initial dose should be sufficiently high to counteract the reduced bioavailability from subcutaneous administration. If an immediate effect is required, the initial dose should be proceeded by an IV bolus injection.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Hepflush-10 :
    - Storage information not available
    Hep-Lock:
    - Storage information not available
    Hep-Lock U/P:
    - Storage information not available
    Monoject Prefill Advanced Heparin Lock Flush:
    - Storage information not available
    SASH Normal Saline and Heparin:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Do not use therapeutic heparin when appropriate blood coagulation tests for monitoring cannot be performed at appropriate intervals. If the coagulation test is excessively prolonged or hemorrhage occurs, discontinue heparin immediately. Periodic platelet and hematocrit monitoring is recommended throughout the course of heparin therapy.
     
    Significant elevation in aminotransferases (AST and ALT) have occurred in a high percentage of patients (including healthy subjects) who received heparin. Use caution when interpreting the clinical implications of elevated hepatic enzymes in patients receiving heparin.
     
    Heparin may prolong the one-stage prothrombin time. Hence, when given with warfarin, allow at least 5 hours after the last IV dose or 24 hours after the last subcutaneous dose of heparin to elapse before blood is drawn to obtain an accurate prothrombin time.

    Asthma, benzyl alcohol hypersensitivity, corn hypersensitivity, heparin hypersensitivity, porcine protein hypersensitivity, sulfite hypersensitivity

    Heparin is contraindicated in patients with known heparin hypersensitivity; reserve heparin in these patients for clearly life-threatening situations. Heparin is derived from porcine tissue; therefore, use of heparin is contraindicated in patients with porcine protein hypersensitivity. Because heparin is derived from animal tissue, monitor for signs and symptoms of hypersensitivity when it is used in patients with a history of allergy. Heparin solutions containing dextrose may be contraindicated in patients with corn hypersensitivity. Some heparin preparations contain sulfites, which can induce a life-threatening allergic response in some patients. Use such heparin products with extreme caution in patients with known sulfite hypersensitivity; sulfite sensitivity reactions tend to occur more frequently in patients with asthma. Some heparin preparations contain benzyl alcohol as a preservative; avoid these formulations in patients with benzyl alcohol hypersensitivity.

    Heparin-induced thrombocytopenia (HIT), thrombocytopenia

    Heparin is contraindicated in patients with severe thrombocytopenia and in those with a history of heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis (HITT). Heparin may be used safely in patients with mild nonimmune thrombocytopenia (platelets more than 100,000/mm3), which may remain stable or reverse with continued treatment. However, use an alternative anticoagulant and avoid all sources of heparin in patients with a history of immune-mediated heparin-induced thrombocytopenia because these patients can develop thrombotic complications during heparin therapy. Because it may not be possible to differentiate asymptomatic, nonimmune thrombocytopenia from immune-mediated thrombocytopenia, monitor platelet count closely. If the platelet count falls below 100,000/mm3 or recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternate anticoagulant. Thrombosis in association with thrombocytopenia may indicate white-clot syndrome, which can lead to severe thromboembolic complications. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy; evaluate patients presenting with thrombocytopenia or thrombosis after heparin discontinuation for HIT or HITT. Avoid future heparin use in patients with a diagnosis of HIT or HITT, especially within 3 to 6 months of diagnosis and while patients test positive for antibodies.

    Aneurysm, bleeding, coagulopathy, diverticulitis, endocarditis, head trauma, hemophilia, hypertension, hypotension, inflammatory bowel disease, lumbar puncture, menstruation, peptic ulcer disease, spinal anesthesia, surgery, vaginal bleeding

    Heparin is contraindicated in patients with uncontrollable bleeding (with the exception of bleeding associated with disseminated intravascular coagulation). Avoid use of heparin in the presence of major bleeding, unless the benefits of therapy outweigh the potential risks. Fatal hemorrhages have occurred with the use of heparin. Hemorrhage can occur at virtually any site in patients receiving heparin. Blood coagulation tests should be performed before and regularly during therapy. Consider the possibility of a hemorrhagic event with an unexplained fall in hematocrit, hypotension, or any other unexplained symptom. Use heparin with extreme caution in a patient with conditions that might increase the risk of hemorrhage. These may include subacute bacterial endocarditis; dissecting aortic aneurysm; peptic ulcer disease; diverticulitis; inflammatory bowel disease; liver disease; coagulopathy; hemophilia; thrombocytopenia; menstruation; threatened abortion or other abnormal vaginal bleeding; severe hypertension; head trauma; major surgery or trauma, especially involving eye, brain, or spinal cord; during or immediately after a lumbar puncture or spinal anesthesia; tube drainage of stomach or small intestine; and increased capillary permeability. Patients with hereditary antithrombin III deficiency receiving antithrombin III therapy are also at risk for hemorrhage with concurrent heparin use; reduce the heparin dose during concomitant use to reduce the risk of bleeding. Monitor all patients receiving heparin closely for easy bruising or petechiae, which can precede signs of hemorrhage such as nosebleed, hematuria, or tarry stools.

    Intracranial bleeding

    In patients with acute intracranial bleeding, the American College of Chest Physicians (ACCP) recommends the initial use of pneumatic compression devices for prevention of DVT and PE. In stable patients, low-dose subcutaneous heparin may be initiated as soon as the second day after the onset of intracranial hemorrhage (ICH). This represents a Grade 2C recommendation by ACCP, and assumes a relatively low degree of risk aversion.

    Fever, infection, myocardial infarction, neoplastic disease, thrombophlebitis

    Increased resistance to heparin is frequently encountered in patients with fever, thrombosis, thrombophlebitis, infection with thrombosing tendencies, myocardial infarction, neoplastic disease, postsurgical patients, and patients with antithrombin III deficiency. Monitor coagulation tests closely in such patients; heparin dose adjustments based on anti-factor Xa concentrations may be necessary.

    Disseminated intravascular coagulation (DIC), hepatic disease, renal disease

    Use heparin cautiously in patients with underlying hepatic disease as these patients often have coagulopathies and are at increased risk for anticoagulant-associated bleeding. Patients with inherited antithrombin deficiency usually have antithrombin concentrations 40% to 60% of normal but may have resistance to heparin and require higher doses to achieve the desired therapeutic response. Patients with acquired antithrombin deficiency, as seen with severe hepatic disease (e.g., cirrhosis), renal disease (e.g., nephrotic syndrome), or disseminated intravascular coagulation (DIC), may not respond to heparin.

    Infants, neonates, premature neonates

    When using heparin lock flush solutions to maintain catheter patency, the 100 unit/mL concentration should not be used in neonates or in infants who weigh less than 10 kg because of the risk of systemic anticoagulation. While systemic anticoagulation is not common with the use of heparin flushes for line patency in general, clinicians should use caution and carefully monitor small infants and other at risk patients receiving multiple flushes per day regardless of the heparin concentrations used. Extreme caution should be used during the preparation, dispensing, and administration of heparin flushes, heparin-containing fluids, and therapeutic doses of heparin for pediatric patients. Heparin injection is available in a wide range of concentrations. Fatal hemorrhages have occurred in pediatric patients (including neonates) due to medication errors in which concentrated 1 mL heparin injection vials were administered rather than 1 mL 'catheter lock flush' vials. To confirm correct vial choice during preparation and prior to administration, carefully inspect labels of heparin injection vials. Use preservative-free heparin formulations in neonates. Multiple dose vials contain benzyl alcohol as a preservative and should be avoided in this population. A 'gasping syndrome' characterized by CNS depression, metabolic acidosis, and gasping respirations has been associated with benzyl alcohol dosages more than 99 mg/kg/day in neonates. However, the minimum amount of benzyl alcohol at which toxicity may occur is unknown and low-birth weight and premature neonates may be more likely to develop toxicity. Normal therapeutic heparin doses would deliver benzyl alcohol at amounts lower than those reported with 'gasping syndrome'; however, the clinician should be aware of the toxic potential, especially if other drugs containing benzyl alcohol are administered.

    Geriatric

    Geriatric patients, especially females, may have higher plasma concentrations of heparin and longer activated partial thromboplastin time (aPTT) compared to patients younger than 60 years of age following similar doses. A higher incidence of bleeding in elderly patients older than 60 years, especially females, has been reported. Elderly patients may require lower doses of heparin.

    Intramuscular administration, intramuscular injections

    Heparin is not intended for intramuscular administration. Severe large hematomas caused by accidental puncture of an IM vein may occur. Avoid intramuscular injections of other medications to patients receiving heparin. IM injections may cause bleeding, bruising, or hematomas.

    Pregnancy

    In published reports, heparin exposure during pregnancy did not result in increased risk of adverse maternal or fetal outcomes in humans. No teratogenicity was seen in animal studies where animals were given approximately 10 times the maximum recommended human dose during organogenesis; however, increased resorptions were reported. Consider the benefits and risks of heparin to a pregnant woman and possible risks to the fetus when using heparin during pregnancy. Heparin does not cross the placental barrier. When indicated, only preservative-free formulations should be administered. Benzyl alcohol has been associated with serious adverse events and death, particularly in neonates and infants.

    Breast-feeding

    There are no data on the presence of heparin in human milk, the effects on the breast-fed infant, or the effects on milk production. Due to its large molecular weight, heparin is not likely to be excreted in human breast milk, and any heparin in milk would not be orally absorbed by a nursing infant. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for heparin and any potential adverse effects on the breast-fed infant from heparin or from the underlying maternal condition. When indicated, only preservative-free formulations should be administered. Benzyl alcohol has been associated with serious adverse events and death, particularly in neonates and infants.

    ADVERSE REACTIONS

    Severe

    bone fractures / Delayed / 2.0-3.0
    ocular hemorrhage / Delayed / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    hematemesis / Delayed / Incidence not known
    retroperitoneal bleeding / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    stroke / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    hyperkalemia / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known

    Moderate

    thrombocytopenia / Delayed / 0-30.0
    elevated hepatic enzymes / Delayed / 10.0
    melena / Delayed / Incidence not known
    hyphema / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    vaginal bleeding / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    subdural hematoma / Early / Incidence not known
    hematoma / Early / Incidence not known
    prolonged bleeding time / Delayed / Incidence not known
    hypoaldosteronism / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    erythema / Early / Incidence not known
    skin ulcer / Delayed / Incidence not known
    hyperlipidemia / Delayed / Incidence not known
    priapism / Early / Incidence not known

    Mild

    purpura / Delayed / Incidence not known
    epistaxis / Delayed / Incidence not known
    petechiae / Delayed / Incidence not known
    headache / Early / Incidence not known
    vomiting / Early / Incidence not known
    rhinitis / Early / Incidence not known
    lacrimation / Early / Incidence not known
    fever / Early / Incidence not known
    chills / Rapid / Incidence not known
    nausea / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    injection site reaction / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) The use of abciximab within 7 days of use an oral anticoagulant is contraindicated unless the patient's prothrombin time is less than or equal to 1.2 times the control value. Because abciximab inhibits platelet aggregation, additive effects may be seen when abciximab is given in combination with other agents that affect hemostasis such as other platelet inhibitors (e.g. aspirin, ASA, clopidogrel, dipyridamole, ticlopidine), thrombolytic agents (e.g. alteplase, reteplase, streptokinase), and anticoagulants (e.g., heparin, warfarin). However, in clinical trials with abciximab, aspirin and heparin were administered concomitantly. The bleeding risk is significantly increased with concurrent abciximab and thrombolytic therapy; the risks of combination therapy should be weighed against the potential benefits. The GUSTO V study evaluated reduced-dose reteplase in combination with full dose abciximab, in comparison to full dose reteplase alone in patients with acute myocardial infarction (MI); all patients received concurrent aspirin and heparin therapy. The combination regimen was associated with a two-fold increase in moderate to severe non-intracranial bleeding complications, including spontaneous GI bleeding. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Although NSAIDs lacks platelet inhibitory effects, an increased risk for GI bleeding is possible when NSAIDs are administered during abciximab therapy.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ado-Trastuzumab emtansine: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Aliskiren; Amlodipine: (Minor) Concomitant use of amlodipine with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Concomitant use of amlodipine with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Aliskiren; Valsartan: (Minor) Concomitant use of valsartan with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Alprostadil: (Moderate) Caution is advised with the concomitant administration of alprostadil injection for dilation of the ductus arteriosis and heparin infusions. Coadministration resulted in a 140% increase in partial thromboplastin time and a 120% increase in thrombin time in a study of 12 healthy volunteers receiving alprostadil 90 mcg infusion over 3 hours and heparin 5000 units. Monitor patients for increased bleeding if these agents are used together.
    Alteplase, tPA: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Altretamine: (Moderate) Due to the thrombocytopenic effects of altretamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Amiloride: (Moderate) Simultaneous use of a potassium-sparing diuretic with heparin can increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitoring of serum potassium is recommended as indicated.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Simultaneous use of a potassium-sparing diuretic with heparin can increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitoring of serum potassium is recommended as indicated.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Amlodipine: (Minor) Concomitant use of amlodipine with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Amlodipine; Atorvastatin: (Minor) Concomitant use of amlodipine with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Amlodipine; Benazepril: (Minor) Concomitant use of amlodipine with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Concomitant use of amlodipine with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Concomitant use of amlodipine with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium. (Minor) Concomitant use of valsartan with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Amlodipine; Olmesartan: (Minor) Concomitant use of amlodipine with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Amlodipine; Telmisartan: (Minor) Concomitant use of amlodipine with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Amlodipine; Valsartan: (Minor) Concomitant use of amlodipine with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium. (Minor) Concomitant use of valsartan with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Anagrelide: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin.
    Angiotensin-converting enzyme inhibitors: (Moderate) Angiotensin-converting enzyme inhibitors decrease aldosterone secretion, leading to small increases in serum potassium levels. Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, potassium salts, and heparin, should be given cautiously, if at all, to patients receiving lisinopril, with frequent serum potassium monitoring. Hyperkalemia can cause serious, sometimes fatal, arrhythmias.
    Anthracyclines: (Moderate) Due to the thrombocytopenic effects of anthracyclines, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, rivaroxaban is a mild P-glycoprotein (P-gp) inhibitor and doxorubicin is a major substrate of P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of rivaroxaban and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Antithrombin III: (Major) As a regulator of hemostasis, antithrombin III (AT III) may increase bleeding risk in patients receiving heparin concomitantly. The anticoagulant effect of heparin is enhanced by concurrent treatment with AT III in patients with hereditary AT III deficiency. In addition, the half-life of AT III may be altered during concomitant administration with anticoagulants. Thus, in order to avoid bleeding, the heparin dosage may need to be reduced during treatment with AT III. 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.
    Antithymocyte Globulin: (Moderate) Drugs that can cause thrombocytopenia, such as antithymocyte globulin, may lead to an increased risk of bleeding when given concurrently with anticoagulants.
    Apixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Aprotinin: (Moderate) If an activated clotting time is used to determine the effectiveness of heparin anticoagulation, the prolongation of ACT by aprotinin may lead to an overestimation of the degree of anticoagulation, thereby leading to inadequate anticoagulation.
    Argatroban: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with heparin.
    Arsenic Trioxide: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Aspirin, ASA: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Carisoprodol: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Dipyridamole: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
    Aspirin, ASA; Omeprazole: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Oxycodone: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Pravastatin: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Azelastine; Fluticasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Beclomethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Betamethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Betrixaban: (Major) Avoid concurrent use of betrixaban with heparin 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.
    Bevacizumab: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Bismuth Subsalicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Bivalirudin: (Major) An additive risk of bleeding may be seen in patients receiving or other anticoagulants in combination with heparin.
    Budesonide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Budesonide; Formoterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Bupropion; Naltrexone: (Moderate) Give the extended-release injectable suspension of naltrexone cautiously to patients taking anticoagulants. Steps should be taken to avoid the risk of bleeding and hematoma formation following intramuscular injection.
    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.
    Cardiac glycosides: (Minor) Digitalis (e.g., cardiac glycosides like digoxin or digitoxin) may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    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.
    Cetirizine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Cetirizine; Pseudoephedrine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Chlorambucil: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Choline Salicylate; Magnesium Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Chondroitin; Glucosamine: (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.
    Ciclesonide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Cilostazol: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Clofarabine: (Moderate) Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Clopidogrel: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants. In healthy volunteers receiving heparin, clopidogrel does not alter the effect of heparin on coagulation parameters or require adjustment of the heparin dose. In addition, heparin has no effect on inhibition of platelet aggregation induced by clopidogrel. Nevertheless, the safety of this combination has not been established and concomitant administration of clopidogrel with heparin should be undertaken with caution.
    Cod Liver Oil: (Major) Cod liver oil should be used only with caution and with frequent monitoring in patients on concurrent anticoagulants. In a limited number of patients, the hypoprothrombinemic response to warfarin was increased following large doses of vitamin A. Additionally, omega-3 fatty acids contained in cod liver oil may inhibit platelet aggregation. Theoretically, the risk of bleeding may be increased, but some studies that combined omega-3 fatty acids and anticoagulant 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 to 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 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 cod liver oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly. (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.
    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.
    Corticorelin, Ovine: (Major) The use of a heparin solution to maintain IV cannula patency during corticorelin stimulation tests is not recommended. A possible interaction between corticorelin and heparin may have been responsible for a major hypotensive reaction that occurred after corticorelin administration.
    Corticosteroids: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Corticotropin, ACTH: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Cortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    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) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Dalteparin: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants (e.g., heparin) in combination with dalteparin.
    Danaparoid: (Severe) An additive risk of bleeding may be seen in patients receiving other anticoagulants (e.g., heparin, warfarin) in combination with danaparoid. Monitoring of anticoagulant therapy by prothrombin time and Thrombotest is unreliable within 5 hours after danaparoid administration.
    Danazol: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Dasatinib: (Moderate) Due to the thrombocytopenic and possible platelet inhibiting effects of dasatinib, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, dasatinib is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. Coadministration may result in increases in rivaroxaban exposure and may increase bleeding risk. Caution should be exercised if patients are required to take anticoagulants concomitantly with dasatinib.
    Decitabine: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    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: (Severe) 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.
    Deflazacort: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Denileukin Diftitox: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Desirudin: (Major) Any agent which may enhance the risk of hemorrhage should generally be discontinued before initiating desirudin therapy, including anticoagulants. If coadministration cannot be avoided, close clinical and laboratory monitoring should be conducted. During prophylaxis of venous thromboembolism with desirudin, concomitant treatment with heparins [including unfractionated and low-molecular weight heparins (LMWHs)] or dextrans is not recommended. The effects of desirudin and unfractionated heparins on prolongation of aPTT are additive.
    Desloratadine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Desloratadine; Pseudoephedrine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Desmopressin: (Minor) Desmopressin has been shown to have an additive effect on the anticoagulant activity of heparin. Caution should be used when coadministering these agents.
    Desvenlafaxine: (Major) Platelet aggregation may be impaired by desvenlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Dexamethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    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) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
    Drospirenone; Estradiol: (Minor) Chronic heparin therapy may predispose a patient to develop hyperkalemia; this risk may be increased in patients receiving drospirenone concomitantly. Monitoring of serum potassium during the 1st month of concurrent therapy with drospirenone is recommended.
    Drospirenone; Ethinyl Estradiol: (Minor) Chronic heparin therapy may predispose a patient to develop hyperkalemia; this risk may be increased in patients receiving drospirenone concomitantly. Monitoring of serum potassium during the 1st month of concurrent therapy with drospirenone is recommended.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Chronic heparin therapy may predispose a patient to develop hyperkalemia; this risk may be increased in patients receiving drospirenone concomitantly. Monitoring of serum potassium during the 1st month of concurrent therapy with drospirenone is recommended.
    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.
    Duloxetine: (Major) Platelet aggregation may be impaired by duloxetine 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. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Edoxaban: (Major) Avoid concurrent use of edoxaban with heparin 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: (Major) 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.
    Eplerenone: (Minor) Heparin may potentially increase the risk of hyperkalemia in patients receiving eplerenone. Monitor serum potassium if eplerenone is used concurrently with drugs with potential to induce hyperkalemia.
    Epoprostenol: (Moderate) When used concurrently with anticoagulants, epoprostenol may increase the risk of bleeding.
    Eptifibatide: (Moderate) Concomitant use of eptifibatide and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. In clinical trials with eptifibatide, aspirin and heparin were administered concomitantly. Eptifibatide has been administered with a thrombolytic agent in a small number of patients. In the IMPACT II study, 15 patients received a thrombolytic agent with the 135/0.5 dosing regimen, 2 of whom experienced a major bleed. In the PURSUIT study, 40 patients who received eptifibatide (180 mcg/kg bolus, then 2 mcg/kg/min) also received a thrombolytic agent, 10 of whom experienced a major bleed. In another acute MI study (n=181), eptifibatide (180 mcg/kg bolus, then up to 2 mcg/kg/min for up to 72 hours) was administered concomitantly with streptokinase (1.5 mU over 60 min). At the highest studied infusion rates (1.3 to 2 mcg/kg/min), eptifibatide was associated with an increase in the incidence of bleeding and transfusions compared to the incidence seen with streptokinase alone.
    Esomeprazole; 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.
    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.
    Estramustine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    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.
    Famotidine; 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.
    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.
    Fexofenadine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Fexofenadine; Pseudoephedrine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    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.
    Floxuridine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Fludrocortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Flunisolide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluorouracil, 5-FU: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    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.
    Fluticasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluticasone; Salmeterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluticasone; Vilanterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Fondaparinux: (Major) Discontinue heparin 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.
    Formoterol; Mometasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fulvestrant: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Garlic, Allium sativum: (Moderate) Garlic produces clinically significant antiplatelet effects so additive bleeding may occur if anticoagulants are given in combination with garlic, allium sativum. In regard to warfarin, no substantial clinical data are available to support or deny a potential for interaction; the data are limited to a random case report. 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. Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.
    Gefitinib: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    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: (Major) Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants. Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants (e.g., warfarin), aspirin, ASA or other platelet inhibitors, or thrombolytic agents. A patient who had been taking aspirin 325 mg/day PO for 3 years following coronary-artery bypass surgery, developed spontaneous bleeding into his eye after taking a standardized extract of Ginkgo biloba (Ginkoba commercial product) 40 mg PO twice daily for one week. The patient stopped taking the ginkgo but continued taking the aspirin with no recurrence of bleeding over a 3-month period. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic ginkgo biloba ingestion.
    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.
    Guarana: (Major) Guarana has been shown to possess minor antiplatelet activity and, therefore, concurrent use of guarana and anticoagulants or platelet inhibitors should be avoided.
    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.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Simultaneous use of a potassium-sparing diuretic with heparin can increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitoring of serum potassium is recommended as indicated.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Simultaneous use of a potassium-sparing diuretic with heparin can increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitoring of serum potassium is recommended as indicated.
    Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Concomitant use of valsartan with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    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.
    Hydrocortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Hydroxyurea: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibritumomab Tiuxetan: (Moderate) Due to the thrombocytopenic effects of the ibritumomab tiuxetan therapeutic regimen, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. (Moderate) Use potassium phosphates cautiously with heparin, as both drugs increase serum potassium concentrations. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Patients should have serum potassium concentration determinations at periodic intervals.
    Ibrutinib: (Moderate) Use caution with concomitant use of ibrutinib and anticoagulants such as heparin. Bleeding or bruising events occurred in 48% to 63% (grade 3 or 4, 5% to 6%) of patients treated with ibrutinib in clinical trials. The mechanism for bleeding is not well understood, and the risk of hemorrhage may be increased in patients receiving anticoagulant therapy. Closely monitor patients for signs and symptoms of bleeding.
    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; 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.
    Ifosfamide: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Iloprost: (Moderate) When used concurrently with anticoagulants, inhaled iloprost may increase the risk of bleeding.
    Imatinib: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. The manufacturer recommends that patients who require anticoagulation while receiving imatinib should receive low-molecular weight heparin or standard heparin instead of warfarin.
    Indocyanine Green: (Moderate) Heparin products that contain sodium bisulfite may reduce the absorption peak of indocyanine green. Collection of blood samples for analysis should be performed with anticoagulants that do not contain sodium bisulfite.
    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.
    Interferon Alfa-2a: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b; Ribavirin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfacon-1: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    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.
    Kava Kava, Piper methysticum: (Moderate) Kava kava, Piper methysticum does appear to have some anti-thrombotic activity. Persons who are receiving anticoagulants should not take kava kava without first discussing use with their health care professional. Kava kava, Piper methysticum exhibits antithrombotic activity and also inhibits CYP isozymes important in warfarin clearance such as CYP2C9, 2C19, 1A2 and 3A4. Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.
    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 other anticoagulants in combination with heparin.
    Levocetirizine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Levomilnacipran: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) 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. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    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.
    Loratadine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Loratadine; Pseudoephedrine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Magnesium Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Methoxsalen: (Minor) Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Methylprednisolone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    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, RU-486: (Major) When mifepristone, RU-486 (Mifeprex) is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the increased risk of serious bleeding. When mifepristone (Korlym) is used, concurrent use of some anticoagulants should be approached with caution.
    Milnacipran: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) 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. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    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.
    Mometasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    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.
    Naltrexone: (Moderate) Give the extended-release injectable suspension of naltrexone cautiously to patients taking anticoagulants. Steps should be taken to avoid the risk of bleeding and hematoma formation following intramuscular injection.
    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; 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.
    Naproxen; Sumatriptan: (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.
    Natural Antineoplastics: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Nebivolol; Valsartan: (Minor) Concomitant use of valsartan with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Nicotine: (Minor) Nicotine may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance in most patients since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Nilotinib: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted 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.
    Nitroglycerin: (Minor) At high doses, nitroglycerin may interfere with the anticoagulant effect of heparin. Intravenous nitroglycerin can induce heparin resistance. Monitor for lack of heparin efficacy if these drugs are administered concurrently. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    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.
    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.
    Oritavancin: (Severe) Use of intravenous unfractionated heparin for 120 hours (5 days) after oritavancin administration is contraindicated. Although oritavancin has no effect on the coagulation cascade, it does interfere with some coagulation tests by binding to and preventing activation of coagulation by phospholipid reagents commonly used in laboratory tests. The activated partial throboplastin time (aPTT) is artificially elevated for up to 120 hours (5 days) after oritavancin dosing. Consider use of an alternate anticoagulant, as appropriate. For patients who require aPTT monitoring within 120 hours (5 days) after oritavancin use, a non-phospholipid dependent coagulation test, such as Factor Xa, which is chromogenic, may be considered.
    Orlistat: (Moderate) Patients on chronic stable doses of anticoagulants, like heparin, should be monitored closely for changes in coagulation parameters when orlistat is prescribed. Reports of decreased prothrombin, increased INR, and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants.
    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.
    Palifermin: (Moderate) The co-administration of palifermin and unfractionated heparin may result in a 4 to 5-fold increase in palifermin exposure; however, this interaction does not appear to affect the pharmacodynamics of either drug. If heparin is used to maintain an IV line, rinse the line with saline prior to and after palifermin administration. The palifermin AUC value was increased by 5-fold and the mean clearance was decreased by 80% after a single 60 mcg/kg dose of palifermin was administered with therapeutic levels of unfractionated heparin compared with no heparin in 27 healthy subjects. The activated partial thromboplastin time (aPTT) was not affected by this interaction. The palifermin AUC value was increased by 425% and the palifermin clearance, volume of distribution, and half-life was decreased by 76.5%, 73.1%, and 38.8%, respectively, following the administration of palifermin 40 mcg/kg/day for 3 days in combination with therapeutic levels of unfractionated heparin compared with no heparin in 31 healthy subjects. Palifermin administration results in a dose-dependent epithelial cell proliferation that may be assessed by Ki67 immunohistochemical staining. In this study, the pharmacokinetics of palifermin did not affect Ki67 expression in buccal biopsies. The co-administration of palifermin and low-molecular weight heparins (LMWHs), such as enoxaparin and dalteparin, is expected to have a similar interaction.
    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 (e.g., heparin, warfarin) in combination with pentosan.
    Perindopril; Amlodipine: (Minor) Concomitant use of amlodipine with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Phosphorus Salts: (Moderate) Use potassium phosphates cautiously with heparin, as both drugs increase serum potassium concentrations. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Patients should have serum potassium concentration determinations at periodic intervals.
    Photosensitizing agents: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    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.
    Porfimer: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Potassium Phosphate; Sodium Phosphate: (Moderate) Use potassium phosphates cautiously with heparin, as both drugs increase serum potassium concentrations. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Patients should have serum potassium concentration determinations at periodic intervals.
    Potassium: (Moderate) In some cases, heparin can cause hyperkalemia. Chronic heparin therapy may predispose a patient to develop hyperkalemia, especially patients with renal impairment and those receiving potassium-containing medications, such a potassium salts. Monitoring of serum potassium is recommended as indicated.
    Potassium-sparing diuretics: (Moderate) Simultaneous use of a potassium-sparing diuretic with heparin can increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitoring of serum potassium is recommended as indicated.
    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) Based on the mechanism of actions of prasugrel and unfractionated heparin or low-molecular weight heparins (LMWHs), patients receiving these medications in combination may be at increased risk of bleeding. The concurrent use of prasugrel and a single 100 unit/kg intravenous dose of heparin did not disrupt coagulation or the inhibition of platelet aggregation; however, the bleeding time increased compared with monotherapy of either medication. Use caution when administering prasugrel with medications that may increase the risk of bleeding, such as unfractionated heparin or LMWH.
    Prednisolone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Prednisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Protamine: (Severe) Upon contact with heparin, protamine forms a salt, neutralizing the anticoagulant effect of both drugs. Protamine, a strongly basic compound, forms complexes with heparin sodium or heparin calcium, which are acidic compounds. Formation of this complex can result in disruption of the heparin-antithrombin III complex responsible for the anticoagulant activity of heparin. Protamine is used therapeutically to reverse the activity of heparins.
    Rabies Immune Globulin, human RIG: (Minor) The intramuscular rabies immune globulin, human RIG should be administered cautiously to persons receiving anticoagulants. If used concurrently, monitor patients closely for bleeding at the IM injection site. All steps to avoid hematoma formation are recommended.
    Reteplase, r-PA: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Rivaroxaban: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with heparin; the safety of concomitant use has not been studied. If heparin 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.
    Sacubitril; Valsartan: (Minor) Concomitant use of valsartan with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Salicylates: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Salsalate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Sedating H1-blockers: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Selective serotonin reuptake inhibitors: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Sodium Hyaluronate, Hyaluronic Acid: (Moderate) Increased bruising or bleeding at the injection site may occur when using hyaluronate sodium with anticoagulants, including heparin, especially if used within the 3 weeks prior to the procedure.
    Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
    Sorafenib: (Major) Due to the thrombocytopenic effects of sorafenib, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Spironolactone: (Moderate) Simultaneous use of a potassium-sparing diuretic with heparin can increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitoring of serum potassium is recommended as indicated.
    Streptokinase: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    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.
    Taxanes: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Telavancin: (Severe) Concomitant use of intravenous unfractionated heparin infusions and telavancin is contraindicated as the activated partial thromboplastin time (aPTT) test results are expected to be artificially prolonged for 0 to18 hours after telavancin administration. Although telavancin does not increase bleeding risk and has no effect on platelet aggregation, it does interfere with some coagulation tests by binding to and preventing activation of coagulation by phospholipid reagents commonly used in laboratory tests. For patients who require aPTT monitoring while being treated with telavancin, a nonphospholipid dependent coagulation test, such as a Factor Xa (chromogenic) assay, or an alternative anticoagulant not requiring aPTT monitoring may be considered.
    Tenecteplase, TNK-tPA: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Terfenadine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Tetracyclines: (Minor) Tetracyclines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance in most patients since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Thrombolytic Agents: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Ticagrelor: (Moderate) Because ticagrelor inhibits platelet aggregation, a potential additive pharmacodynamic effect for bleeding exists if ticagrelor is given in combination with other agents that affect hemostasis such as heparin. No significant pharmacokinetic changes were seen with ticagrelor was coadministered with heparin 100 international units and enoxaparin 1 mg/kg, and the manufacturer states ticagrelor may be administered with unfractionated heparin and low molecular weight heparins.
    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) Because ticlopidine inhibits platelet aggregation, a potential additive risk for bleeding exists if ticlopidine is given in combination with other agents that affect hemostasis such as anticoagulants. In clinical trials of cardiac stenting, patients were treated with heparin and ticlopidine concomitantly for 12 hours. The tolerance and long term safety of coadministered ticlopidine with these drugs has not been established. Per the manufacturer of ticlopidine, if a patient is switched from an anticoagulant or a thrombolytic agent to ticlopidine, the former drug should be discontinued prior to the administration of ticlopidine.
    Tinzaparin: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with tinzaparin.
    Tipranavir: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in 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, that may have caused or contributed to these events.
    Tirofiban: (Moderate) Concomitant use of tirofiban and other agents that effect hemostasis, such as anticoagulants, other platelet inhibitors, NSAIDs, and thrombolytic agents, may be associated with an increased risk of bleeding. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. In clinical trials with tirofiban, many patients received aspirin and heparin concomitantly. In these studies, the combination of tirofiban with heparin and aspirin has been associated with an increase in bleeding compared to heparin and aspirin alone. While administering tirofiban and heparin, the aPTT should be checked 6 hours after the start of the heparin infusion; heparin should be adjusted to maintain the aPTT approximately 2-times control. No information is available about the concomitant use of tirofiban with thrombolytic agents.
    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).
    Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Trastuzumab: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    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.
    Tretinoin, ATRA: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Triamcinolone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Triamterene: (Moderate) Simultaneous use of a potassium-sparing diuretic with heparin can increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitoring of serum potassium is recommended as indicated.
    Urokinase: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    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.
    Valsartan: (Minor) Concomitant use of valsartan with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Vasopressin, ADH: (Minor) Heparin can decrease the antidiuretic response to vasopressin.
    Venlafaxine: (Major) Platelet aggregation may be impaired by venlafaxine 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. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Verteporfin: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic 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: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Vorinostat: (Moderate) Concomitant use of vorinostat with anticoagulants may result in an additive risk of bleeding due to vorinostat-induced thrombocytopenia; monitor patients closely.
    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 in combination with heparin. Heparin and warfarin therapies often overlap with no serious sequelae, although the risk of bleeding is nonetheless increased. It should be noted that heparin also can prolong prothrombin time. When heparin and warfarin are administered concomitantly, wait at least 5 hours after the last IV heparin dose or 24 hours after the last subcutaneous heparin dose before drawing blood to obtain prothrombin time.

    PREGNANCY AND LACTATION

    Pregnancy

    In published reports, heparin exposure during pregnancy did not result in increased risk of adverse maternal or fetal outcomes in humans. No teratogenicity was seen in animal studies where animals were given approximately 10 times the maximum recommended human dose during organogenesis; however, increased resorptions were reported. Consider the benefits and risks of heparin to a pregnant woman and possible risks to the fetus when using heparin during pregnancy. Heparin does not cross the placental barrier. When indicated, only preservative-free formulations should be administered. Benzyl alcohol has been associated with serious adverse events and death, particularly in neonates and infants.

    There are no data on the presence of heparin in human milk, the effects on the breast-fed infant, or the effects on milk production. Due to its large molecular weight, heparin is not likely to be excreted in human breast milk, and any heparin in milk would not be orally absorbed by a nursing infant. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for heparin and any potential adverse effects on the breast-fed infant from heparin or from the underlying maternal condition. When indicated, only preservative-free formulations should be administered. Benzyl alcohol has been associated with serious adverse events and death, particularly in neonates and infants.

    MECHANISM OF ACTION

    Heparin exerts its anticoagulant action by accelerating the activity of antithrombin III (ATIII) to inactivate thrombin; however, heparin does not lyse existing clots. Approximately one-third of heparin molecules contain a unique pentasaccharide sequence with high-affinity binding to ATIII. The interaction of heparin with ATIII produces a conformational change in ATIII, which accelerates the ability of ATIII to inactivate thrombin (factor IIa), factor Xa, and factor IXa. Of these enzymes, thrombin is the most sensitive to inhibition by heparin/ATIII. Heparin catalyzes the ATIII inactivation of thrombin by acting as a template to which both thrombin and ATIII bind to form a ternary complex. The inactivation of factor Xa does not require the heparin/ATIII complex formation and occurs via binding of ATIII to factor Xa. Heparin molecules must be greater than 18 monosaccharides to bind to thrombin and ATIII simultaneously. Therefore, smaller heparin molecules (i.e., < 18 monosaccharides) are unable to accelerate the inactivation of thrombin by ATIII, but retain their ability to catalyze the inhibition of factor Xa by ATIII. Heparin is unable to inactivate fibrin-bound (i.e., surface) thrombin or factor Xa bound to phospholipid surfaces within the prothrombinase complex. The inability of heparin to inactivate surface-bound thrombin and factor Xa may explain its limited efficacy in patients with unstable angina, high-risk coronary angioplasty, and coronary thrombolysis. At doses higher than those required to stimulate the activity of ATIII, heparin catalyzes the inactivation of thrombin by heparin cofactor II, which does not require interaction with ATIII. Heparin also stimulates the inhibition of thrombin by plasminogen activator inhibitor I, protein C inhibitor, and protease nexin-1 and inhibition of factor Xa by tissue factor pathway inhibitor; however, these proteins are only present in the serum in very small quantities as compared to ATIII.
     
    High doses of heparin also interfere with platelet aggregation, which, in turn, prolongs the bleeding time, although commonly used therapeutic doses heparin do not affect bleeding time. High-molecular-weight heparin fractions have a greater effect on platelet function. It has been shown that the platelet-aggregating activity of heparin can be directly related to its molecular weight.
     
    Fibroblast growth factors (FGF) bind to heparin with high-affinity. Heparin potentiates the effects of FGF by promoting the binding of these factors to their receptors, a transmembrane tyrosine kinase. Fibroblast growth factors stimulate angiogenesis. As opposed to its anticoagulation effects, the activity of heparin on FGF is due to the degree of sulfation and not the size of the molecule.
     
    The variability of anticoagulant response in individuals given fixed doses of heparin is thought to be due to differences between patients in their plasma concentrations of neutralizing plasma proteins and/or heparin-binding proteins (e.g., histidine-rich glycoprotein, vitronectin, lipoproteins, fibronectin, fibrinogen, platelet factor 4, and von Willebrand factor). The response of the aPTT ratio to heparin may be decreased in patients with high levels of factor VIII. These patients may have therapeutic plasma heparin levels at the usual dose of heparin when measured using anti-Xa activity or by protamine sulfate titration, but require very high doses of heparin (> 50,000 International Units/day) to achieve an aPTT > 1.5-times control. Patients with acquired antithrombin deficiency (< 25% normal concentration) may not respond to heparin.

    PHARMACOKINETICS

    Heparin is given parenterally, either intravenously or subcutaneously. Because heparin is highly negatively charged, it binds to a variety of plasma proteins (e.g., histidine-rich glycoprotein, vitronectin, lipoproteins, fibronectin, fibrinogen, platelet factor 4, and von Willebrand factor) some of which are acute-phase reactant proteins that are elevated in acute illness or are released from platelet and endothelial cells as part of the clotting process. The variability in plasma levels of heparin-binding proteins in patients with thromboembolic diseases is responsible for the unpredictable anticoagulant effect of heparin. The nonspecific binding of heparin to proteins and cells may also account for its poor bioavailability when administered subcutaneously in doses of less than 35,000 units/24 hours. When doses more than 35,000 units/24 hours are given, bioavailability is almost complete due to saturation of heparin-binding sites. Because of its large molecular size, heparin does not cross the placenta and is not distributed into breast milk.
     
    Heparin appears to be cleared and metabolized by the reticuloendothelial system. Heparin is metabolized by a rapid, zero-order mechanism, followed by slower first-order renal clearance. In the zero-order phase, heparin is bound to the surface of cells (such as macrophages and endothelial cells) where it is internalized and depolymerized. Because this process is saturable, the plasma half-life of heparin increases from 30 to 150 minutes as the administered dose increases from 25 units/kg to 400 units/kg.
     
    Affected cytochrome P450 isoenzymes: none

    Intravenous Route

    After intravenous administration, response is almost immediate. The anticoagulation half-life of heparin is 1, 2.5, and 5 hours when heparin 100, 400, or 800 units/kg, respectively, is given intravenously.

    Subcutaneous Route

    Individual response after subcutaneous injection varies, but anticoagulant activity is generally delayed for 1 to 2 hours. The nonspecific binding of heparin to proteins and cells may also account for its poor bioavailability when administered subcutaneously in doses of less than 35,000 units/24 hours. When doses more than 35,000 units/24 hours are given, bioavailability is almost complete due to saturation of heparin-binding sites.