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    Factor Xa Inhibitors

    BOXED WARNING

    Epidural anesthesia, lumbar puncture, spinal anesthesia

    Epidural or spinal hemorrhage and subsequent hematomas can occur in patients receiving fondaparinux while epidural anesthesia, spinal anesthesia, or lumbar puncture procedures are performed. The bleeding risk for spinal or epidural hematomas, which may result in permanent or long-term paralysis, may be greater with postoperative use of indwelling epidural catheters, a history of traumatic or repeated epidural or spinal puncture, a history of spinal deformity, a history of spinal surgery, or concomitant use of other drugs affecting hemostasis, such as NSAIDs, platelet inhibitors, or other anticoagulants. The optimal timing between the administration of fondaparinux and neuraxial procedures is not known. If epidural anesthesia, lumbar puncture, or spinal anesthesia is employed, patients should be frequently monitored for symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), and bowel or bladder dysfunction; fondaparinux should be discontinued and appropriate therapy initiated if needed. Clinicians should consider the risk versus benefit of neuraxial intervention in patients anticoagulated or to be anticoagulated.

    DEA CLASS

    Rx

    DESCRIPTION

    Pentasaccharide anticoagulant used SQ for the treatment of DVT and PE, and for DVT and PE prophylaxis in abdominal surgery, hip fracture surgery, and hip and knee replacement surgery. Inhibits factor Xa but not factor IIa (thrombin).

    COMMON BRAND NAMES

    Arixtra

    HOW SUPPLIED

    Arixtra/Fondaparinux/Fondaparinux Sodium Subcutaneous Inj Sol: 0.4mL, 0.5mL, 0.6mL, 0.8mL, 2.5mg, 5mg, 7.5mg, 10mg

    DOSAGE & INDICATIONS

    For the treatment of acute pulmonary embolism (PE) or acute deep venous thrombosis (DVT) in conjunction with warfarin.
    Subcutaneous dosage
    Adults

    The FDA-approved dosage is 5 mg subcutaneously once daily for weight < 50 kg; 7.5 mg subcutaneously once daily for weight 50—100 kg; or 10 mg subcutaneously once daily for weight > 100 kg. Concomitant treatment with warfarin should be initiated as soon as possible, usually within 72 hours. Therapy should be continued for at least 5 days and until a therapeutic warfarin response is established (INR 2.0—3.0). The usual duration of administration of fondaparinux is 5—9 days; up to 26 days has been studied. The MATISSE PI open label study for the treatment of pulmonary embolism used the FDA-approved dosage regimen. Compared to IV unfractionated heparin, fondaparinux demonstrated similar efficacy and safety (n = 2213) in the treatment of acute pulmonary embolism. The mean age in the fondaparinux group for this study was 63 (+/- 16.2) years.

    For deep venous thrombosis (DVT) prophylaxis or pulmonary embolism prophylaxis (PE prophylaxis).
    For DVT or PE prophylaxis following orthopedic surgery including hip fracture surgery, hip replacement surgery, or knee replacement surgery.
    Subcutaneous dosage
    Adults (weight 50 kg or more)

    2.5 mg subcutaneously once daily starting 6 to 8 hours postoperatively after hemostasis has been established. Administration before 6 hours after surgery has been associated an increased risk of major bleeding. The usual duration of administration is 5 to 9 days; up to 11 additional days has been tolerated. For patients undergoing hip surgery extended DVT prophylaxis is indicated up to 24 additional days; up to a total 32 of days peri-operative and extended prophylaxis has been tolerated during clinical trials. This approval is based on the PENTHIFRA PLUS study demonstrating a 96% risk reduction for post-operative venous embolism for extended fondaparinux administration relative to placebo following hip fracture surgery. ACCP guidelines recommend fondaparinux as an alternative to the preferred agent, low molecular weight heparin, as antithrombotic prophylaxis for patients undergoing total hip or total knee replacement surgery or hip fracture surgery. Treatment should continue for a minimum of 10 to 14 days after surgery (Grade 1B Recommendation); up to 35 days is recommended (Grade 2B Recommendation). The use of an intermittent pneumatic compression device (IPCD) during the hospital stay is encouraged (Grade 2C Recommendation).

    For DVT or PE prophylaxis following abdominal surgery in patients who are risk for thromboembolic complications.
    Subcutaneous dosage
    Adults (weight 50 kg or more)

    2.5 mg subcutaneously once daily starting 6 to 8 hours postoperatively after hemostasis has been established. Administration before 6 hours after surgery has been associated with an increased risk of major bleeding. The usual duration of administration is 5 to 9 days; up to 10 days has been administered. Risk factors include those undergoing surgery with general anesthesia lasting more than 45 minutes who are 1) more than 60 years or 2) more than 40 years with at least 1 of the following: neoplastic disease, obesity, chronic obstructive pulmonary disease, inflammatory bowel disease, history of DVT or PE, or congestive heart failure.

    For coronary artery thrombosis prophylaxis† and the prevention of ischemic complications in patients with acute coronary syndrome (ACS)†.
    For patients with ST-segment elevation acute myocardial infarction† (STEMI).
    Intravenous† and Subcutaneous dosage
    Adults

    In patients in whom heparin therapy is not indicated, give 2.5 mg subcutaneously once daily for up to 8 days or until hospital discharge, whichever occurs first. In patients in whom heparin therapy is indicated (scheduled for PCI, undergoing fibrinolysis, or receiving antithrombotic therapy), give 2.5 mg IV† for 1 dose; 24 hours later, begin 2.5 mg subcutaneously once daily for up to 7 days (total of up to 8 days of therapy) or until hospital discharge. In the OASIS-6 study, more than 12,000 patients with STEMI were randomized to up to 8 days of fondaparinux (dosage as listed) or usual care (unfractionated heparin if indicated for 2 days followed by 6 days of placebo, or placebo for 8 days if unfractionated heparin was not indicated). The dose of heparin used was 60 IU/kg IV bolus (Max: 4000 IU) followed by 12 IU/kg/hour continuous IV infusion (Initial max dose: 1000 IU/hour) for 24—48 hours. A reduction in death or reinfarction rate significantly favored fondaparinux treatment at 9 days (8.9% for usual care vs. 7.4% for fondaparinux, HR 0.83, 95% CI 0.73—0.94, p = 0.003), 30 days (11.2% for usual care vs. 9.7% for fondaparinux, HR 0.86, 95% CI 0.77—0.96, p = 0.008), and at 3—6 months (14.8% for usual care vs. 13.4% for fondaparinux, HR 0.88, 95% CI 0.79—0.97, p = 0.008). Subgroup analyses indicate that fondaparinux therapy was beneficial in patients receiving thrombolytics and in those that did not receive any type of reperfusion treatment; however, in those patients undergoing primary PCI, a benefit with fondaparinux was not seen. Bleeding rates were similar between the 2 groups.

    For patients with unstable angina† or non-ST-segment elevation myocardial infarction (NSTEMI)†.
    Subcutaneous dosage
    Adults

    2.5 mg subcutaneously once daily until hospital discharge or for up to 8 days in combination with other standard treatments. In the OASIS-5 study, which enrolled > 20,000 patients with acute coronary syndrome, treatment with fondaparinux was found to be non-inferior to enoxaparin for the primary outcome of death, MI, or refractory ischemia (5.8% incidence for fondaparinux vs. 5.7% for enoxaparin) at 9 days. Furthermore, a significantly reduced incidence of major bleeding (2.2% fondaparinux vs. 4.1% enoxaparin; p < 0.001) and a significantly reduced number of deaths occurred in patients treated with fondaparinux (2.9% fondaparinux vs. 3.5% enoxaparin at 30 days, p = 0.02 and 5.8% fondaparinux vs. 6.5% enoxaparin at 180 days, p = 0.05).The mean duration of fondaparinux in the study was 6 days.

    For the treatment of superficial vein thrombosis† in the legs.
    Subcutaneous dosage
    Adults

    2.5 mg subcutaneously once daily for 45 days.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2.5 mg/day subcutaneously for DVT prophylaxis (in clinical studies, doses greater than 3 mg/day were associated with a significant bleeding risk); up to 10 mg/day subcutaneously for the treatment of PE or DVT.

    Geriatric

    2.5 mg/day subcutaneously for DVT prophylaxis (in clinical studies, doses greater than 3 mg/day were associated with a significant bleeding risk); up to 10 mg/day subcutaneously for the treatment of PE or DVT.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dose adjustment is recommended for patients with mild to moderate hepatic impairment (Child-Pugh Category B). Data are not available for patients with severe hepatic impairment. Monitor patients with hepatic impairment closely for signs and symptoms of bleeding as they may be at higher risk for bleeding during treatment.

    Renal Impairment

    CrCl > 50 mL/min: No dosage adjustment is required; however, use with caution in the elderly.
    CrCl 30—50 mL/min: The manufacturer recommends cautious use; however, no specific dosage guidelines are available.
    CrCl < 30 mL/min: Use is contraindicated.
     
    Intermittent hemodialysis
    Use is contraindicated in patients with CrCl < 30 mL/min.

    ADMINISTRATION

    NOTE: Fondaparinux cannot be used interchangeably with heparin, low molecular weight heparins (LMWH) or heparinoids. All products differ in their manufacturing process, activity, and dosage. Routine laboratory measures of coagulation, such as Prothrombin Time (PT) and Activated Partial Thromboplastin (aPTT) are relatively insensitive measures of fondaparinux activity. International standards of heparin or LMWH are not calibrators to measure anti-factor Xa activity of fondaparinux. If unexpected changes in coagulation parameters occur, fondaparinux should be discontinued.
     
    For storage information, see specific product information within the How Supplied section.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration.

    Intravenous Administration

    Data are limited. This route is not FDA-approved. Fondaparinux was administered intravenously for the first dose in the OASIS-6 trial to patients with an indication for heparin therapy (e.g., undergoing primary PCI, fibrinolysis, or receiving antithrombotic therapy). No further data regarding the safety and efficacy of this route of administration are available.

    Subcutaneous Administration

    Fondaparinux is administered by subcutaneous injection. Do not administer intramuscularly.
    All patients should be evaluated for a bleeding disorder prior to administration of fondaparinux, unless the medication is needed urgently.
    See Dosage section for specific information on timing of subcutaneous administration. Administration of fondaparinux prior to 6 hours following surgery is associated with an increased risk of bleeding.
    Do not mix fondaparinux injection with other injections or parenteral fluids.
    Fondaparinux cannot be used interchangeably with heparin sodium or low molecular weight heparins.
     
    Subcutaneous injection:
    Fondaparinux is available in a single dose, prefilled syringe affixed with an automatic needle protection system. To avoid loss of drug when using the prefilled syringes, do not expel the bubble of air from the syringe before injection. Discard any unused portion of the medication.
    Fondaparinux should be administered by deep subcutaneous injection.
    Wipe the surface of the injection site with an alcohol swab. Follow the manufacturer's instructions for use of the syringe.
    Fondaparinux should be injected into the left or right anterolateral or posterolateral abdominal wall.
    The injection site should be rotated with each injection.

    STORAGE

    Arixtra:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: Fondaparinux cannot be used interchangeably with heparin, low molecular weight heparins (LMWH) or heparinoids. All products differ in their manufacturing process, activity, and dosage. Routine laboratory measures of coagulation, such as Prothrombin Time (PT) and Activated Partial Thromboplastin (aPTT) are relatively insensitive measures of fondaparinux activity. International standards of heparin or LMWH are not calibrators to measure anti-factor Xa activity of fondaparinux. The activity of fondaparinux is expressed as mg of the fondaparinux calibrator. If unexpected changes in coagulation parameters occur, fondaparinux should be discontinued.

    Aneurysm, bleeding, diabetic retinopathy, diverticulitis, endocarditis, GI bleeding, hemophilia, hepatic disease, hypertension, immune thrombocytopenic purpura (ITP), inflammatory bowel disease, peptic ulcer disease, stroke, surgery, vaginal bleeding

    Bleeding is a major risk associated with fondaparinux therapy. Fondaparinux is contraindicated in patients with active major bleeding (e.g., GI bleeding or hemorrhagic stroke in the acute phase) or bacterial endocarditis. Fondaparinux prophylactic therapy is also contraindicated in patients with bodyweight less than 50 kg undergoing hip fracture, hip or knee replacement surgery, or abdominal surgery. In clinical trials for prophylaxis in orthopedic surgery patients, bodyweight less than 50 kg was associated with a two-fold increase in the risk of bleeding versus patients weighing 50 kg or greater (5.4% vs. 2.1%, respectively). Similarly, in patients undergoing abdominal surgery, the incidence of major bleeding was higher in patients weighing less than 50 kg when compared to patients weighing 50 kg or greater (5.3% vs. 3.3%, respectively).  As with other antithrombotic agents, fondaparinux should be used with caution in patients with an increased risk of hemorrhage, such as with infective endocarditis, congenital or acquired bleeding disorders such as hemophilia and immune thrombocytopenic purpura (ITP), history of or active peptic ulcer disease, diverticulitis, inflammatory bowel disease, decreased platelets, recent GI bleeding, hemorrhagic stroke, non-hemorrhagic stroke, angiodysplastic GI disease, dissecting aneurysm, abnormal vaginal bleeding, recent brain, spinal or ophthalmological surgery, severe renal or hepatic disease, uncontrolled hypertension, hypertensive or diabetic retinopathy, or concomitant treatment with platelet inhibitors. To minimize bleeding risk, fondaparinux injection should not be administered earlier than 6 to 8 hours after surgery; administration before 6 hours after surgery has been associated with an increased risk of major bleeding.[40227]

    Intramuscular administration

    Fondaparinux sodium should be injected subcutaneously; it is not suitable for intramuscular administration. Other intramuscular injections should be administered cautiously to patients receiving fondaparinux. IM injections may cause bleeding, bruising, or hematoma formation in patients who are anticoagulated.

    Geriatric

    Use fondaparinux cautiously in geriatric patients, particularly those 75 years of age and older. Renal clearance in this population is reduced by roughly 25% and accumulation of the unbound, active drug may lead to serious adverse events. Assess renal parameters prior to the use of fondaparinux in the elderly and pay careful attention to dosing directions and the use of concomitant medications that affect hemostasis. The risk of major bleeding increases with age. During clinical prophylaxis trials in patients with hip fracture, or hip or knee replacement surgery, major bleeding in 2.2% of those 65 to 74 years of age and in 2.7% of those 75 years and older, compared to occurred in 1.8% of adults less than 65 years of age. Similarly, during clinical prophylaxis trials with fondaparinux after abdominal surgery, major bleeding occurred in 3.2% of patients 65 to 74 years of age, and in 5% of those 75 years of age or older versus 3% in younger adults. In the DVT and PE clinical trials, the risk of fondaparinux-associated major bleeding increased with age: 0.6% in patients less than 65 years, 1.6% in those 65 to 74 years, and 2.1% in those 75 years and older. According to the Beers Criteria, fondaparinux should be avoided in geriatric patients with a creatinine clearance (CrCl) less than 30 mL/minute due to an increased risk of bleeding.

    Heparin-induced thrombocytopenia (HIT), thrombocytopenia

    The presence of thrombocytopenia associated with a positive in-vitro test for anti-platelet antibody in the presence of fondaparinux is a contraindication to the use of fondaparinux. Thrombocytopenia has occurred with fondaparinux. The manufacturer suggests that if platelet counts fall below 100,000 mm3, fondaparinux should be discontinued. In clinical trials, patients with platelet counts < 100,000 mm3 were excluded from study. Fondaparinux should be used cautiously in patients with a history of heparin-induced thrombocytopenia (HIT). Theoretically, fondaparinux should not cause HIT because it does not bind to platelet factor 4. In-vitro cross-reactivity with antibodies that produce heparin-induced thrombocytopenia has not been observed. Clinical trials are needed to determine if fondaparinux is a safe alternative to heparin in patients at risk for HIT.

    Renal disease, renal failure, renal impairment

    The presence of severe renal disease, severe renal impairment (CrCl less than 30 mL/minute), or renal failure are contraindications to the use of fondaparinux. Fondaparinux should be used cautiously in patients with moderate renal function (CrCl 30 to 50 mL/minute) as prolonged anticoagulation may occur. All patients receiving fondaparinux should be regularly evaluated for adequate renal function and the drug should be discontinued if severe renal impairment or labile renal function occurs. Adequate renal function is required as fondaparinux is excreted primarily as the unchanged drug. Accumulation of the active drug greatly increases the risk for a major bleed. Major bleeding was defined in clinical studies as fatal bleeding, nonfatal bleeding in a critical organ, bleeding requiring reoperation, or overt bleeding with a bleeding index of 2 or more. Occurrence of major bleeds in clinical trials for fondaparinux prophylaxis in hip fracture, hip replacement, or knee replacement surgery was 1.6%, 2.4%, 3.8%, and 4.8% in patients with normal, mild, moderate, or severe renal impairment, respectively. In patients treated with fondaparinux for DVT and PE prophylaxis after abdominal surgery, major bleeding occurred in 2.1%, 3.6%, 6.7%, and 7.1% of patients with normal, mild, moderate, and severe renal impairment, respectively. Occurrences of major bleeding in patients fondaparinux for treatment of DVT and PE with normal renal function, mild renal impairment, moderate renal impairment, and severe renal impairment have been found to be 0.4%, 1.6%, 2.2%, and 7.3%, respectively. In clinical trials, patients with a serum creatinine of more than 2 mg/dL were excluded from study randomization.

    Latex hypersensitivity

    The needle guard for the Arixtra prefilled syringe contains dry natural latex rubber and may cause reactions in patients with latex hypersensitivity.

    Labor, obstetric delivery, pregnancy

    A clear association with fondaparinux and fetal adverse developmental outcomes has not been demonstrated with available data from published literature and postmarketing reports. Fondaparinux plasma concentrations obtained from 4 pregnant women treated with fondaparinux and their newborn infants demonstrated low placental transfer of fondaparinux. Use of fondaparinux may increase the risk of bleeding in the fetus or neonate; monitor neonates for bleeding. In a study of 5 pregnant women treated with fondaparinux 2.5 mg/day during the third trimester, 4 women had increased anti-factor Xa activity in the cord blood; anti-factor Xa clotting times were 37.5 to 50.9 seconds. Umbilical cord plasma fondaparinux concentrations were one-tenth the concentration in maternal plasma. No infants experienced adverse effects. Fondaparinux use during labor or obstetric delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Monitor pregnant women receiving fondaparinux carefully for evidence of bleeding or unexpected changes in coagulation parameters. Consider use of a shorter acting anticoagulant as delivery approaches. Clinical practice guidelines recommend low molecular weight heparin for the prevention and treatment of venous thromboembolism during pregnancy.

    Breast-feeding

    There are no data on the presence of fondaparinux in human milk or the effects on milk production. Limited clinical data preclude a clear determination of the risk of fondaparinux to an infant during breast-feeding. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for fondaparinux and any potential adverse effects on the breast-fed infant from fondaparinux or the mother's underlying condition. Clinical practice guidelines suggest alternative anticoagulants, such as warfarin, unfractionated heparin, or low molecular weight heparin, rather than fondaparinux during breast-feeding.

    Children, infants, neonates

    Safe and effective use of fondaparinux in neonates, infants, and children has not been established. The risk of bleeding during treatment with fondaparinux is increased in patients who weigh < 50 kg. This may be a particular safety concern for the use of fondaparinux in children.

    Anticoagulant therapy, thrombolytic therapy

    Fondaparinux should be used with caution in patients receiving other anticoagulant therapy (e.g., warfarin), thrombolytic therapy (e.g., alteplase, reteplase, streptokinase), and/or platelet inhibitors (e.g., aspirin, ticlopidine) due to the potential increased risk of bleeding.

    Dental disease, dental work

    Patients who are anticoagulated with fondaparinux are at increased risk of bleeding during dental procedures. Patient should inform health care providers of anticoagulant therapy prior to having dental work performed. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

    History of angioedema

    Fondaparinux is contraindicated in patients with a history of angioedema or history of serious hypersensitivity reactions to fondaparinux, including anaphylactoid/anaphylactic reactions.

    Intramuscular injections

     Intramuscular injections of other medications should not be administered to patients receiving fondaparinux. IM injections may cause bleeding, bruising, or hematomas.

    Epidural anesthesia, lumbar puncture, spinal anesthesia

    Epidural or spinal hemorrhage and subsequent hematomas can occur in patients receiving fondaparinux while epidural anesthesia, spinal anesthesia, or lumbar puncture procedures are performed. The bleeding risk for spinal or epidural hematomas, which may result in permanent or long-term paralysis, may be greater with postoperative use of indwelling epidural catheters, a history of traumatic or repeated epidural or spinal puncture, a history of spinal deformity, a history of spinal surgery, or concomitant use of other drugs affecting hemostasis, such as NSAIDs, platelet inhibitors, or other anticoagulants. The optimal timing between the administration of fondaparinux and neuraxial procedures is not known. If epidural anesthesia, lumbar puncture, or spinal anesthesia is employed, patients should be frequently monitored for symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), and bowel or bladder dysfunction; fondaparinux should be discontinued and appropriate therapy initiated if needed. Clinicians should consider the risk versus benefit of neuraxial intervention in patients anticoagulated or to be anticoagulated.

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / Incidence not known
    ocular hemorrhage / Delayed / Incidence not known
    hematemesis / Delayed / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    retroperitoneal bleeding / Delayed / Incidence not known
    spinal hematoma / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    anemia / Delayed / 19.6-19.6
    hypokalemia / Delayed / 4.2-4.2
    hypotension / Rapid / 3.5-3.5
    confusion / Early / 3.1-3.1
    bleeding / Early / 2.0-3.0
    thrombocytopenia / Delayed / 0-3.0
    hematoma / Early / 2.8-2.8
    hematuria / Delayed / Incidence not known
    melena / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    insomnia / Early / 5.0-5.0
    infection / Delayed / 4.9-4.9
    dizziness / Early / 3.6-3.6
    purpura / Delayed / 3.5-3.5
    headache / Early / 2.0-2.0
    ecchymosis / Delayed / Incidence not known
    petechiae / Delayed / Incidence not known
    epistaxis / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    rash / Early / 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Acetaminophen; Aspirin: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Acetaminophen; Aspirin; Diphenhydramine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Alteplase: (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.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Amlodipine; Celecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Anagrelide: (Moderate) lthough 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.
    Antithrombin III: (Major) Discontinue antithrombin III 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.
    Apixaban: (Major) Avoid concomitant use of apixaban and with other anticoagulants due to the increased risk for bleeding. Short-term overlaps in anticoagulation therapy may be necessary for patients transitioning from one anticoagulant to another. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if the use of multiple anticoagulants is necessary.
    Argatroban: (Major) Discontinue thrombin inhibitors before starting fondaparinux due to the increased bleeding risk, unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding.
    Aspirin, ASA: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Caffeine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Betrixaban: (Major) Avoid use of betrixaban with fondaparinux due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and other anticoagulants are used concomitantly. Coadministration of betrixaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with betrixaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from betrixaban.
    Bismuth Subsalicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Bivalirudin: (Major) Discontinue thrombin inhibitors before starting fondaparinux due to the increased bleeding risk, unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding.
    Bupivacaine; Meloxicam: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Caplacizumab: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
    Carbenicillin: (Moderate) Some penicillins (e.g., carbenicillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Celecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Celecoxib; Tramadol: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Chlorambucil: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Choline Salicylate; Magnesium Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Cytarabine, ARA-C: (Moderate) Due to the thrombocytopenic effects of pyrimidine analogs, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Dabigatran: (Major) Avoid use of dabigatran with fondaparinux due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if dabigatran and other anticoagulants are used concomitantly. Coadministration of dabigatran and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with dabigatran and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from dabigatran.
    Dalteparin: (Major) Discontinue dalteparin 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.
    Danaparoid: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with fondaparinux. If possible, agents that enhance the risk of bleeding should be discontinued prior to initiation of fondaparinux therapy.
    Danazol: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Dasatinib: (Moderate) Monitor for evidence of bleeding if coadministration of dasatinib and anticoagulants is necessary. Dasatinib can cause serious and fatal bleeding. Concomitant anticoagulants may increase the risk of hemorrhage.
    Deferasirox: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Defibrotide: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
    Desirudin: (Major) Discontinue thrombin inhibitors before starting fondaparinux due to the increased bleeding risk, unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding.
    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.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any anticoagulants. There is an additive risk of beeding.
    Edoxaban: (Major) Avoid concurrent use of edoxaban with fondaparinux due to the increased bleeding risk. Discontinue edoxaban before starting fondaparinux unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding. 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) Discontinue enoxaparin 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.
    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.
    Esterified Estrogens; Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
    Etodolac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Factor X: (Major) The actions of factor X are likely to be counteracted by direct and indirect factor Xa inhibitors such as apixaban, edoxaban, rivaroxaban, and fondaparinux.
    Fenoprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    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.
    Garlic, Allium sativum: (Moderate) Garlic produces clinically significant antiplatelet effects so additive risk of bleeding may occur if anticoagulants are given in combination. Avoid concurrent use of herbs which interact with anticoagulants when possible. If garlic dietary supplements are taken, monitor the INR or other appropriate parameters to attain clinical and anticoagulant endpoints. In regard to warfarin, published data are limited to a random case report; however, the product labeling for warfarin includes garlic as having potential for interaction due to additive pharmacologic activity. A case of spontaneous spinal epidural hematoma, attributed to dysfunctional platelets from excessive garlic use in a patient not receiving concomitant anticoagulation, has been reported.
    Ginger, Zingiber officinale: (Moderate) Additive bleeding may occur if anticoagulants are given in combination with ginger, zingiber officinale. Ginger inhibits thromboxane synthetase (platelet aggregation inducer) and is a prostacyclin agonist. Patients taking ginger and an anticoagulant should be monitored closely for bleeding.
    Ginkgo, Ginkgo biloba: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and fondaparinux as an increased bleeding risk may occur. Although data are mixed, ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with ginkgo biloba, with or without concomitant drug therapy.
    Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if co-administered with anticoagulants (e.g., enoxaparin, heparin, warfarin, and others) thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, cilostazol and others). Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with any of these agents. Exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin; stability of the diet can be an important factor in maintaining anticoagulation goals. Occult sources of vitamin K include green tea and green tea dietary supplements. Published data are limited in regard to this interaction. A patient with previous INRs of 3.2. and 3.79 on a dose of 7.5mg daily of warfarin (goal INR 2.5 to 3.5) had an INR of 1.37. One month later, the patient's INR was 1.14. The patient admitted that he had started consuming 0.51 gallon of green tea daily approximately one week prior to the INR of 1.37. The patient denied noncompliance and other changes in diet, medications, or health. The patient discontinued green tea and one week later his INR was 2.55. While the amount of vitamin K in a single cup of brewed green tea may not be high (0.03 mcg/100 g), the actual amount may vary from cup to cup depending on the amount of tea leaves used, the length of time the tea bags are allowed to brew, and the volume of tea consumed. Additionally, if a patient drinks multiple cups of tea per day, the amount of vitamin K could reach significance. It is recommended that patients on warfarin maintain a stable intake of green tea.
    Hemin: (Major) Because hemin has exhibited transient, mild anticoagulant effects during clinical studies, concurrent use of anticoagulants should be avoided. The extent and duration of the hypocoagulable state induced by hemin has not been established.
    Heparin: (Major) 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.
    Hydrocodone; Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with coagulation such as anticoagulants; the risk of bleeding may be increased. If coadministration with anticoagulants is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
    Ibrutinib: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as fondaparinux may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Famotidine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Oxycodone: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Pseudoephedrine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Iloprost: (Moderate) When used concurrently with anticoagulants, inhaled iloprost may increase the risk of bleeding.
    Indomethacin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
    Intravenous Lipid Emulsions: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Ketoprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ketorolac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Lansoprazole; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Lepirudin: (Major) Discontinue thrombin inhibitors before starting fondaparinux due to the increased bleeding risk, unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding.
    Lomustine, CCNU: (Moderate) Due to the bone marrow suppressive and thrombocytopenic effects of lomustine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Magnesium Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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.
    Methenamine; Sodium Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Methoxsalen: (Minor) Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs such as increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants such as warfarin until data confirming the safety of MSM in patients taking these drugs are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving warfarin should be observed for increased bleeding.
    Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
    Mifepristone: (Contraindicated) When mifepristone is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the risk of serious bleeding.
    Miltefosine: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
    Mycophenolate: (Moderate) Mycophenolate may causes thrombocytopenia and increase the risk for bleeding. Agents which may lead to an increased incidence of bleeding in patients with thrombocytopenia include anticoagulants.
    Nabumetone: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Nandrolone Decanoate: (Moderate) Androgens can enhance the effects of anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain prothrombin time at the desired therapeutic level. When anabolic steroid or androgen therapy is started or stopped in patients on anticoagulant therapy, close monitoring is required. Additionally, nandrolone decanoate may generate a pharmacodynamic interaction with warfarin by independently affecting the activity of circulating coagulation proteins. Androgens reduce the amount or activity of circulating coagulant proteins thereby enhancing the anticoagulant effect of warfarin.
    Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Esomeprazole: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Pseudoephedrine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Nintedanib: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Nonsteroidal antiinflammatory drugs: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    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.
    Orlistat: (Moderate) Patients on chronic stable doses of anticoagulants, like fondaparinux, 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.
    Pentosan: (Major) Discontinue pentosan 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. Pentosan is a weak anticoagulant. Pentosan has one-fifteenth the anticoagulant activity of heparin.
    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.
    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) Concomitant use of prasugrel and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
    Prothrombin Complex Concentrate, Human: (Major) The actions of factor X are likely to be counteracted by direct and indirect factor Xa inhibitors such as apixaban, edoxaban, rivaroxaban, and fondaparinux.
    Reteplase, r-PA: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Rivaroxaban: (Major) Discontinue rivaroxaban 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.
    Rofecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Salicylates: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, 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) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Selective serotonin reuptake inhibitors: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like fondaparinux. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Serotonin norepinephrine reuptake inhibitors: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like fondaparinux. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
    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.
    Sumatriptan; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Telavancin: (Moderate) Telavancin has no effect on coagulation or platelet aggregation; however, caution is advised when administering telavancin concurrently with anticoagulants as telavancin may interfere with laboratory tests used in monitoring these medications. The coagulation tests affected by telavancin include prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), activated clotting time, and coagulation based factor Xa tests. When measured shortly after completion of a telavancin infusion, the results of these tests are increased; however, the effects of telavancin on these tests dissipate over time as plasma concentrations of telavancin decrease. Therefore, when administering telavancin in conjunction with anticoagulants ensure that blood samples for these coagulation tests are collected as close as possible to the patient's next telavancin dose.
    Tenecteplase: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Thrombin Inhibitors: (Major) Discontinue thrombin inhibitors before starting fondaparinux due to the increased bleeding risk, unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding.
    Thrombolytic Agents: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Ticagrelor: (Moderate) There have been no documented pharmacokinetic interactions of fondaparinux with other drugs. However, an additive risk of bleeding may be seen in patients receiving platelet inhibitors.
    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. 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 fondaparinux. If possible, agents that enhance the risk of bleeding should be discontinued prior to initiation of fondaparinux therapy.
    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, may be associated with an increased risk of bleeding.
    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.
    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.
    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.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with anticoagulants is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease clotting could decrease the efficacy of verteporfin therapy.
    Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. In addition, both vilazodone and warfarin are highly protein bound, which may result in displacement of warfarin from protein binding sites and an increased anticoagulant effect. It would be prudent for clinicians to monitor the INR and clinical status of the patient closely if vilazodone is added to or removed from the regimen of a patient stabilized on warfarin.
    Vorapaxar: (Major) Avoid concomitant use of vorapaxar and 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.
    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) Discontinue warfarin before starting fondaparinux due to the increased bleeding risk, unless these agents are essential, such as in the early treatment of deep venous thrombosis or pulmonary embolism. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no data on the presence of fondaparinux in human milk or the effects on milk production. Limited clinical data preclude a clear determination of the risk of fondaparinux to an infant during breast-feeding. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for fondaparinux and any potential adverse effects on the breast-fed infant from fondaparinux or the mother's underlying condition. Clinical practice guidelines suggest alternative anticoagulants, such as warfarin, unfractionated heparin, or low molecular weight heparin, rather than fondaparinux during breast-feeding.

    MECHANISM OF ACTION

    Fondaparinux exerts antithrombotic activity as a result of antithrombin III (ATIII)-mediated selective inhibition of factor Xa. Fondaparinux is a copy of the antithrombin III binding area of heparin. When fondaparinux binds to ATIII, a permanent conformation change in the ATIII molecule allows an increased affinity for factor Xa. The increased affinity potentiates ATIII's ability to inhibit factor Xa by roughly 300-fold. Neutralization of factor Xa interrupts the blood coagulation cascade that leads to thrombin formation and thrombus development. A single fondaparinux molecule is recycled and re-binds to several consecutive ATIII molecules. The structurally changed ATIII-Xa complex is then cleared from circulation. The anti-Xa activity of fondaparinux reaches a maximum value in roughly 3 hours. Fondaparinux does not inactivate thrombin (factor IIa) and has no known effect on platelet function. At recommended doses, fibrinolytic activity or bleeding time is not altered. An antidote to reverse bleeding effects of fondaparinux is not available; however, one is under investigation.

    PHARMACOKINETICS

    Fondaparinux is administered by subcutaneous (SC) injection. Fondaparinux exhibits dose-dependent, linear pharmacokinetics. Distribution is primarily in the blood. Fondaparinux exhibits a small volume of distribution of 7—11 L as evidenced by 94% in-vitro protein binding specifically to antithrombin III (ATIII). Significant binding to other proteins, including platelet factor 4 or red blood cells does not occur. Metabolism of fondaparinux appears to be negligible as the majority of the unbound drug is excreted unchanged in the urine. In healthy individuals <= 75 years of age, 77% of a parenteral dose is excreted unchanged in the urine in 72 hours. An elimination half-life of roughly 18 hours and a sustainable plasma level allows once-daily dosing.

    Subcutaneous Route

    After subcutaneous administration, fondaparinux is rapidly absorbed with 100% bioavailability. A single dose maximum concentration of 0.34 mg/L occurs in roughly 2 hours. A peak steady-state concentration of 0.39—0.50 mg/L is reached within 3 hours post-dose.