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    Antithrombin III

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    Nov.20.2024

    Antithrombin III

    Indications/Dosage

    Labeled

    • deep venous thrombosis (DVT)
    • deep venous thrombosis (DVT) prophylaxis
    • pulmonary embolism
    • pulmonary embolism prophylaxis

    Off-Label

      † Off-label indication

      For the treatment of deep venous thrombosis (DVT) or pulmonary embolism (PE) in patients with a deficiency in antithrombin III

      Intravenous dosage (plasma-derived antithrombin III, Thrombate III)

      Adults

      Dosage can be calculated from the following formula: Units required (International Units) = [desired concentration - baseline AT III concentration] x weight (kg)/1.4% (International Units/kg). In general, calculate initial loading dose to elevate the plasma AT III concentration to 120%, assuming an expected rise over the baseline AT III concentration of 1.4% (functional activity) per International Unit/kg of AT III administered. If the in vivo recovery differs from an anticipated rise of 1.4% for each International Units/kg administered, modify the formula accordingly. Plasma concentrations between 80% to 120% may be maintained with maintenance doses of 60% of the initial loading dose given approximately every 24 hours as needed. However, adjustments in the maintenance dose and/or interval between doses should be made based on actual plasma AT III concentrations achieved. In many cases, it is desirable to raise the AT III concentration to normal and maintain this concentration for 2 to 8 days, depending on the indication for treatment, type and extensiveness of surgery, the patient's medical condition and history, and the clinician's judgment.

      For deep venous thrombosis (DVT) prophylaxis or pulmonary embolism prophylaxis in patients with a hereditary deficiency in antithrombin III who are undergoing surgical or obstetrical procedures

      Intravenous dosage (human antithrombin III, Thrombate III)

      Adults

      Dosage can be calculated from the following formula: Units required (International Units) = [desired concentration - baseline AT III concentration] x weight (kg)/1.4% (International Units/kg). In general, calculate initial loading dose to elevate the plasma AT III concentration to 120%, assuming an expected rise over the baseline AT III concentration of 1.4% (functional activity) per International Unit/kg of AT III administered. If the in vivo recovery differs from an anticipated rise of 1.4% for each International Units/kg administered, modify the formula accordingly. Plasma concentrations of 80% to 120% may be maintained with maintenance doses of 60% of the initial loading dose, given approximately every 24 hours as needed. However, adjustments in the maintenance dose and/or interval between doses should be made based on actual plasma AT III concentrations achieved. In many cases, it is desirable to raise the AT III concentration to normal and maintain this concentration for 2 to 8 days, depending on the indication for treatment, type and extensiveness of surgery, the patient's medical condition and history, and the clinician's judgment.

      Intravenous dosage (recombinant antithrombin III, ATryn)

      Adults undergoing surgical procedures

      Give a loading dose over 15 minutes starting 24 hours before the procedure, then, immediately start a continuous infusion of the maintenance dose. The loading dose is calculated using the following formula: (International Units/hour) = [(100 - baseline antithrombin activity concentration)/2.3] X Body Weight (kg). The maintenance dose is calculated using the following formula: (International Units/hour) = [(100 - baseline antithrombin activity concentration)/10.2] X Body Weight (kg). The treatment goal is to restore and maintain functional antithrombin activity concentrations of 80% to 120% of normal (0.8 to 1.2 International Units/mL). Continue treatment continue anticoagulation is established.

      Adult females undergoing obstetrical procedures

      Give a loading dose over 15 minutes starting 24 hours before the procedure, then, immediately start a continuous infusion of the maintenance dose. The loading dose is calculated using the following formula: (International Units/hour) = [(100 - baseline antithrombin activity concentration)/1.3] X Body Weight (kg). The maintenance dose is calculated using the following formula: (International Units/hour) = [(100 - baseline antithrombin activity concentration)/5.4] X Body Weight (kg). The treatment goal is to restore and maintain functional antithrombin activity concentrations of 80% to 120% of normal (0.8 to 1.2 International Units/mL). Continue treatment continue anticoagulation is established.

      Therapeutic Drug Monitoring

      Plasma-derived antithrombin (Thrombate III):

      The baseline antithrombin III (AT III) concentration is usually expressed as a percentage of a reference plasma. To calculate the in vivo recovery, plasma AT III concentrations should be measured prior to the infusion and 20 minutes after the infusion (peak). Plasma concentrations of AT III should also be measured at least every 12 hours and immediately before the next infusion to maintain plasma AT III concentrations more than 80% (range: 80% to 120%). Plasma AT III concentrations should be monitored more frequently if the half-life of AT III is shortened, such as after surgery, with hemorrhage or acute thrombosis, and during intravenous heparin administration. Antithrombin III concentrations should be measured before and 20 minutes after each infusion until predictable peak and trough concentrations have been achieved. Do not use immunoassays to measure AT III concentrations; immunoassays do not detect all hereditary AT deficiencies. Measure AT III concentrations by amidolytic assays using chromogenic substrates or by clotting assays.[30131]

       

      Recombinant antithrombin III (ATryn):

      The AT III activity concentration should be obtained 2 hours after initiation of treatment. If the AT III concentration is less than 80%, increase the maintenance infusion by 30% and recheck the AT III activity concentration in 2 hours. If the AT III concentration is 80% to 120%, no dose adjustment is needed, and the AT III activity concentration should be checked again in 6 hours. If the AT III activity concentration is more than 120%, decrease the maintenance infusion by 30%, and recheck the AT III activity concentration in 2 hours. The AT III activity concentration should be checked immediately after surgery or delivery as a rapid decrease in AT III activity concentration may occur during these procedures. If the AT III activity concentration is less than 80%, give an additional loading dose utilizing the last available AT III activity concentration in the formula. Thereafter, restart the maintenance dose at the same rate of infusion as before the bolus.

      Maximum Dosage Limits

        Patients with Hepatic Impairment Dosing

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

        Patients with Renal Impairment Dosing

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

        † Off-label indication
        Revision Date: 11/20/2024, 01:31:00 AM

        References

        30131 - Thrombate III (antithrombin III) package insert. Elkhart, IN: Bayer Corporation; 2016 Feb.

        How Supplied

        Antithrombin III Lyophilisate for solution for injection

        ATryn 1750units Powder for Injection (67386-0521) (Lundbeck Inc. ) (off market)ATryn 1750units Powder for Injection package photo

        Antithrombin III Lyophilisate for solution for injection

        ATryn 1750units Powder for Injection (42976-0121) (rEVO Biologics, Inc.) null

        Antithrombin III Lyophilisate for solution for injection

        ATryn 525units Powder for Injection (42976-0121) (rEVO Biologics, Inc.) null

        Antithrombin III Lyophilisate for solution for injection

        Thrombate III 1000units Powder for Injection (00026-0603) (Bayer Pharmaceuticals Corporation) (off market)

        Antithrombin III Lyophilisate for solution for injection

        Thrombate III 1000units Powder for Injection (13533-0603) (Grifols USA, LLC) (off market)

        Antithrombin III Lyophilisate for solution for injection

        Thrombate III 500units Powder for Injection (00026-0603) (Bayer Pharmaceuticals Corporation) (off market)

        Antithrombin III Lyophilisate for solution for injection

        Thrombate III 500units Powder for Injection (13533-0603) (Grifols USA, LLC) (off market)

        Antithrombin III Lyophilisate for solution for injection

        Thrombate III 500units Powder for Injection (13533-0602) (Grifols USA, LLC) (off market)

        Antithrombin III Lyophilisate for solution for injection

        Thrombate III 500units Powder for Injection (13533-0605) (Grifols USA, LLC) null

        Antithrombin III Lyophilisate for solution for injection

        Thrombate III 500units Powder for Injection (13533-0606) (Grifols USA, LLC) null

        Antithrombin III Lyophilisate for solution for injection

        Thrombate III 500units Powder for Injection (13533-0602) (Grifols USA, LLC) null

        Description/Classification

        Description

        Antithrombin, or Antithrombin III (AT III), is another name for heparin cofactor I, a factor in plasma necessary for heparin to exert its anticoagulant activity. AT III is a natural anticoagulant synthesized in the liver. It plays a major role in the regulation of hemostasis by inhibiting thrombin; factors IXa, Xa, XIa, and XIIa; kallikrein; and plasmin. AT III deficiency predisposes patients to venous thromboembolic events by impairing the clearance of activated coagulation factors. Thrombate III is AT III concentrate produced from pooled human plasma and indicated in patients with hereditary antithrombin III deficiency for treatment and prevention of thromboembolism, including peri-operative and peri-partum thromboembolism. Another product, ATryn, is the first biological agent produced by genetically engineered animals (goats) and the first recombinant human antithrombin. ATryn is produced utilizing recombinant DNA technology in which the DNA coding sequence for human antithrombin has been introduced along with a mammary gland-specific DNA sequence that directs the expression of antithrombin into the milk of goats. ATryn is indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients.

        Classifications

        • Blood and Blood Forming Organs
          • Antihemorrhagics
            • Antifibrinolytics
              • Proteinase Inhibitors
                • Coagulation Inhibitors
        Revision Date: 11/20/2024, 01:31:00 AM

        References

        Administration Information

        General Administration Information

        For storage information, see the specific product information within the How Supplied section.

        Route-Specific Administration

        Injectable Administration

        Intravenous Administration

        • Reconstitute, administer, and handle the administration set and needle for human antithrombin III (Thrombate III) cautiously. Place needles in a sharps container, and discard all equipment including any unused product in an appropriate container. Human antithrombin III (Thrombate III) is made from human plasma and may contain infectious agents.
        • Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

         

        Reconstitution of human antithrombin III (Thrombate III):

        • Bring vials of human antithrombin III and diluent to room temperature.
        • Remove flip tops and swab bottle stoppers using aseptic technique. Then, remove the tamperproof cover from the double-ended transfer needle and penetrate the bottle containing the diluent (10 mL of Sterile Water for Injection).
        • Remove the other side of the cartridge, invert the diluent bottle at a 45 degree angle and penetrate the bottle containing human antithrombin III. The diluent will be automatically transferred into the concentrate.
        • After removing the diluent bottle containing the needle, gently swirl the concentrate bottle until the powder is completely dissolved. Avoid excessive foaming.
        • Each vial contains approximately 500 International Units of antithrombin III potency. The resulting solution will have a final concentration of approximately 50 International Units/mL.
        • Once reconstituted, human antithrombin III should be given alone, without mixing with other agents or diluting solutions.
        • Storage: Do not refrigerate after reconstitution.[30131]

         

        Reconstitution of recombinant antithrombin III (ATryn):

        • Bring vials to room temperature not more than 3 hours prior to reconstitution.
        • Reconstitute vials with 10 mL Sterile Water for Injection. DO NOT SHAKE. Each vial of recombinant antithrombin III contains approximately 1,750 International Units of antithrombin III potency.
        • Do not use if solution contains particulates or is discolored or cloudy.

         

        Intravenous infusion:

        Human antithrombin III (Thrombate III):

        • Administer within 3 hours after reconstitution. With filter needle in place, insert a syringe into the reconstituted bottle and withdraw the solution into the syringe. If the dose requires using more than 1 vial, the contents of multiple vials may be drawn into the same syringe. To administer, replace the filter needle with an appropriate injection needle.
        • The rate of administration should be individualized; however, intravenous administration of the entire dose over 10 to 20 minutes is generally well-tolerated.

         

        Recombinant antithrombin III (ATryn):

        • Withdraw reconstituted solution from appropriate number of vials into a sterile disposable syringe for intravenous administration or add reconstituted solution to an infusion bag containing 0.9% Sodium Chloride Injection to a final concentration of 100 International Units/mL.
        • Administer using an infusion set with a 0.22 micron in-line filter.
        • Administer loading dose as a 15-minute infusion immediately followed by a continuous infusion of the maintenance dose.
        • Storage: Solution contained in syringe or further diluted should be used within 8 to 12 hours when stored at room temperature (20 to 25 degrees C; 68 to 77 degrees F).

        Clinical Pharmaceutics Information

        From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
          Revision Date: 11/20/2024, 01:31:00 AM

          References

          30131 - Thrombate III (antithrombin III) package insert. Elkhart, IN: Bayer Corporation; 2016 Feb.

          Adverse Reactions

          Moderate

          • bleeding
          • blurred vision
          • chest pain (unspecified)
          • dyspnea
          • elevated hepatic enzymes
          • hematoma
          • hematuria
          • hepatitis

          Mild

          • chills
          • dizziness
          • dysgeusia
          • fever
          • flushing
          • infection
          • injection site reaction
          • nausea
          • pruritus
          • urticaria

          Severe

          • GI bleeding

          Human antithrombin III (Thrombate III) is well tolerated. Only occasional, mild, and transient reactions have been noted. Although manufacturing practices are designed to reduce the risk of transmitting viral infection, human antithrombin III is prepared from pooled human plasma, which may contain the causative agents of hepatitis and other viral diseases. However, no cases of HIV seroconversion have been described with the use of human antithrombin III.[30131]

          In clinical studies involving human antithrombin III (Thrombate III), dizziness (12%), chest pain (unspecified) (3%), chest discomfort (9%), and dyspnea (3%) were reported. Non-cardiac chest pain was reported in 2% of patients treated with recombinant antithrombin III (ATryn).[30131] [34885]

          Bleeding has been reported in patients receiving antithrombin III. In clinical trials involving recombinant antithrombin III (ATryn), the most common adverse event reported was bleeding (5% or more); GI bleeding (reported as intra-abdominal hemorrhage), hemarthrosis, hematoma, and hematuria were each reported in 2% of patients. Hematoma and wound secretion were reported in 3% (n = 1) of patients receiving human antithrombin III (Thrombate III) and described as severe.[30131] [34885]

          In clinical trials involving human antithrombin III (Thrombate III), chills and fever occurred in 3% of patients and pain (cramps) in 6% of patients.[30131]

          Injection site reaction (5% or more) was among the most common adverse reactions reported with recombinant antithrombin III (ATryn); application site pruritus and flushing were reported in 2% of patients.[34885] Urticaria was reported in 3% of patients during clinical trials of human antithrombin III (Thrombate III).[30131]

          In clinical trials, elevated hepatic enzymes occurred in 2% of patients receiving recombinant antithrombin III (ATryn).[34885] Nausea (9%), dysgeusia (6%), and intestinal dilatation (3%) were reported in patients receiving human antithrombin III (Thrombate III).[30131]

          During human antithrombin III (Thrombate III) clinical trials, blurred vision was reported in 3% of patients.[30131]

          Revision Date: 11/20/2024, 01:31:00 AM

          References

          30131 - Thrombate III (antithrombin III) package insert. Elkhart, IN: Bayer Corporation; 2016 Feb.34885 - Atryn™ (recombinant antithrombin) package insert. Framingham, MA: GTC Biotherapeutics, Inc., 2009 Feb.

          Contraindications/Precautions

          Absolute contraindications are italicized.

          • goat milk protein hypersensitivity
          • breast-feeding
          • labor
          • obstetric delivery
          • pregnancy
          • viral infection

          Human antithrombin III (Thrombate III) is derived from pooled human plasma. As with other products derived from or purified with human blood components, the remote possibility of contamination with bacterial or viral infection, including hepatitis, or Creutzfeldt-Jakob disease (CJD) exists in patients receiving human antithrombin III. Screening plasma donors for prior exposure to certain viruses, testing for the presence of viruses, and inactivating and/or reducing viruses has reduced the risk of transmission of infectious agents; however, none of the processes are completely effective. There is also the possibility that unknown infectious agents are present in the pooled product. All infections thought to have been transmitted by human antithrombin III should be reported to the manufacturer.[30131]

          ATryn is contraindicated in patients with known goat and goat milk protein hypersensitivity. ATryn is a recombinant human product derived from genetically engineered goats in which the DNA coding sequence for human antithrombin has been introduced along with a mammary gland specific DNA sequence, directing the expression of antithrombin into the milk. The goats that produce recombinant antithrombin are contained in a closed, USDA certified scrapie-free herd and are controlled for specific pathogens. Immunological reactions to the recombinant protein, goat antithrombin, or goat-milk proteins are possible. Assays have been developed to detect antibodies to these proteins. No confirmed immunological reactions were seen in clinical trials. The manufacturer has developed a post-marketing patient registry to collect additional data on the immunogenetic potential of recombinant antithrombin III. Healthcare providers are encouraged to call Ovation Pharmaceuticals (1—800—455—1141) for further instruction on this registry. ATryn is not formulated with human plasma proteins and therefore not associated with the risks of human plasma-derived products (e.g., viral or bacterial contamination).

          Use antithrombin III during pregnancy only if clearly needed.[30131] [34885] There are no data in pregnant women to determine a drug-associated risk with plasma-derived antithrombin III (Thrombate). It is not known whether plasma-derived antithrombin III can cause fetal harm when administered to a pregnant woman or if can affect reproductive capacity. Reproduction studies in rats and rabbits at doses up to 4 times the human dose have revealed no evidence of impaired fertility or harm to the fetus due to plasma-derived antithrombin III. During labor and obstetric delivery, suspend heparin or low molecular weight heparin and continue plasma-derived antithrombin III administration.[30131] Recombinant antithrombin III (ATryn) is classified as pregnancy category C. There are no adequate and well-controlled studies in pregnant women. In clinical trials of hereditary antithrombin III deficient patients, 22 pregnant women were treated with recombinant antithrombin III around parturition; no adverse reactions were reported in infants born to these women.[34885]

          It is not known whether plasma-derived antithrombin III (Thrombate III) is excreted in human milk, the effects on the breast-fed infant, or the effects on milk production. Recombinant antithrombin III (ATryn) is present in breast milk at concentrations 1/50 to 1/100 of that found in blood, which is estimated to be equivalent to that found in normal lactating women and is not thought to be harmful to breast-fed infants. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for antithrombin III and any potential adverse effects on the breast-fed infant from antithrombin III or the mother's underlying condition.[30131] [34885]

          Revision Date: 11/20/2024, 01:31:00 AM

          References

          30131 - Thrombate III (antithrombin III) package insert. Elkhart, IN: Bayer Corporation; 2016 Feb.34885 - Atryn™ (recombinant antithrombin) package insert. Framingham, MA: GTC Biotherapeutics, Inc., 2009 Feb.

          Mechanism of Action

          Antithrombin III (AT III) belongs to the serpine family of serine protease inhibitors and plays a major role in the regulation of hemostasis by inhibiting thrombin; factors IXa, Xa, XIa, and XIIa; kallikrein; and plasmin. The activity of AT III results from the interaction between its active arginine site and the active serine residue on thrombin that forms a covalent bond with 1:1 stoichiometry. The binding of heparin to a lysine residue on AT III induces a conformational change at the arginine-reactive center of AT III, thereby enhancing the rate of thrombin:AT III complex formation 1000-fold. Thus, AT III is important in mediating the major antithrombotic effect of heparin. AT III also neutralizes Factor Xa by forming a complex that is rapidly removed from the circulation.

           

          In clinical situations that reduce AT III activity levels (e.g., DIC, sepsis, trauma, surgery), heparin may become less effective. In most cases, the decrease in AT III activity associated with heparin administration (about 15%) is negligible. However, it has been shown that, in cases of disseminated intravascular coagulation, heparin responsiveness depends on AT III activity and that normalization of AT III activity level reduces the amount of heparin required for adequate anticoagulation. The ability of AT III to bind thrombin and Factor Xa is increased 300—1000 fold when it is concurrently bound to heparin. Therefore, in patients with suspected heparin resistance, it may be desirable to raise the AT III activity level to 80—100% prior to and during heparin therapy. Although controlled trials are lacking, use of AT III concentrate in conjunction with extracorporeal circulation may improve the coagulation profile and reduce the amount of heparin necessary for anticoagulation.[25406]

           

          Hereditary AT III deficiency results in an increased risk of thromboembolism in affected individuals, particularly during high-risk procedures such as surgery, trauma, and during the peri-partum period. The administration of plasma-derived and recombinant AT III to patients with AT III deficiency results in normalization of AT III activity levels.

          Revision Date: 11/20/2024, 01:31:00 AM

          References

          25406 - Hashimoto K, Yamagishi M, Sasaki T, et al. Heparin and antithrombin III levels during cardiopulmonary bypass: correlation with subclinical plasma coagulation. Ann Thorac Surg 1994;58:799-804.

          Pharmacokinetics

          Antithrombin III is administered intravenously. Surgical procedures, bleeding, and concomitant heparin administration may influence the pharmacokinetic properties of AT III; therefore, AT III monitoring should be performed for all patients receiving therapy to ensure adequate AT III levels are obtained.

          Route-Specific Pharmacokinetics

          Intravenous Route

          • Plasma-derived antithrombin III (Thrombate III): The time to fall to 50% of the peak plasma concentration after initial administration is 22.3 hours and the biological half-life of antithrombin III is about 2.5 days based on immunologic assays and 3.8 days based on functional assays.[30131]
          • Recombinant antithrombin III (ATryn): An open-label, single dose study assessed the pharmacokinetic parameters of recombinant AT III (50 or 100 International Units/kg) in 15 patients aged 18 years or older. The administration of 1 International Unit/kg of recombinant AT III raises the plasma AT III level by 2.24% and 1.94% for the 50 and 100 International Units/kg dose, respectively. The mean half-life of recombinant AT III was shorter than plasma-derived AT III at 11.6 hours and 17.7 hours for the 50 and 100 International Units/kg dose of recombinant AT III, respectively, compared to 2.5 days for plasma-derived AT III. Additionally, the mean clearance of recombinant AT III was more rapid than plasma-derived antithrombin. The mean residence time (average time a drug resides in the body after a given dose) was 16.2 hours and 20.5 hours for the 50 and 100 International Units/kg dose, respectively.

          Special Populations

          Other

          • Plasma-derived antithrombin III (Thrombate III): The half-life of antithrombin III has been reported to be shortened in patients after surgery, hemorrhage or acute thrombosis, and during heparin or low molecular weight heparin administration. Monitor antithrombin concentrations more frequently in these situations.[30131]
          Revision Date: 11/20/2024, 01:31:00 AM

          References

          30131 - Thrombate III (antithrombin III) package insert. Elkhart, IN: Bayer Corporation; 2016 Feb.

          Pregnancy/Breast-feeding

          labor, obstetric delivery, pregnancy

          Use antithrombin III during pregnancy only if clearly needed.[30131] [34885] There are no data in pregnant women to determine a drug-associated risk with plasma-derived antithrombin III (Thrombate). It is not known whether plasma-derived antithrombin III can cause fetal harm when administered to a pregnant woman or if can affect reproductive capacity. Reproduction studies in rats and rabbits at doses up to 4 times the human dose have revealed no evidence of impaired fertility or harm to the fetus due to plasma-derived antithrombin III. During labor and obstetric delivery, suspend heparin or low molecular weight heparin and continue plasma-derived antithrombin III administration.[30131] Recombinant antithrombin III (ATryn) is classified as pregnancy category C. There are no adequate and well-controlled studies in pregnant women. In clinical trials of hereditary antithrombin III deficient patients, 22 pregnant women were treated with recombinant antithrombin III around parturition; no adverse reactions were reported in infants born to these women.[34885]

          breast-feeding

          It is not known whether plasma-derived antithrombin III (Thrombate III) is excreted in human milk, the effects on the breast-fed infant, or the effects on milk production. Recombinant antithrombin III (ATryn) is present in breast milk at concentrations 1/50 to 1/100 of that found in blood, which is estimated to be equivalent to that found in normal lactating women and is not thought to be harmful to breast-fed infants. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for antithrombin III and any potential adverse effects on the breast-fed infant from antithrombin III or the mother's underlying condition.[30131] [34885]

          Revision Date: 11/20/2024, 01:31:00 AM

          References

          30131 - Thrombate III (antithrombin III) package insert. Elkhart, IN: Bayer Corporation; 2016 Feb.34885 - Atryn™ (recombinant antithrombin) package insert. Framingham, MA: GTC Biotherapeutics, Inc., 2009 Feb.

          Interactions

          Level 1 (Severe)

          • Defibrotide
          • Mifepristone

          Level 2 (Major)

          • Alteplase
          • Apixaban
          • Argatroban
          • Betrixaban
          • Bivalirudin
          • Caplacizumab
          • Dabigatran
          • Dalteparin
          • Danazol
          • Edoxaban
          • Enoxaparin
          • Fondaparinux
          • Hemin
          • Heparin
          • Ibritumomab Tiuxetan
          • Omacetaxine
          • Pentosan
          • Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements)
          • Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved)
          • Reteplase, r-PA
          • Rivaroxaban
          • Tenecteplase
          • Vorapaxar
          • Warfarin

          Level 3 (Moderate)

          • Acetaminophen; Aspirin
          • Acetaminophen; Aspirin, ASA; Caffeine
          • Acetaminophen; Aspirin; Diphenhydramine
          • Acetaminophen; Ibuprofen
          • Ado-Trastuzumab emtansine
          • Aminosalicylate sodium, Aminosalicylic acid
          • Amlodipine; Celecoxib
          • Anagrelide
          • Aspirin, ASA
          • Aspirin, ASA; Butalbital; Caffeine
          • Aspirin, ASA; Caffeine
          • Aspirin, ASA; Caffeine; Orphenadrine
          • Aspirin, ASA; Carisoprodol; Codeine
          • Aspirin, ASA; Citric Acid; Sodium Bicarbonate
          • Aspirin, ASA; Dipyridamole
          • Aspirin, ASA; Omeprazole
          • Aspirin, ASA; Oxycodone
          • Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate
          • Bismuth Subsalicylate
          • Bismuth Subsalicylate; Metronidazole; Tetracycline
          • Bupivacaine; Meloxicam
          • Butalbital; Aspirin; Caffeine; Codeine
          • Celecoxib
          • Celecoxib; Tramadol
          • Chlorambucil
          • Chlorpheniramine; Ibuprofen; Pseudoephedrine
          • Choline Salicylate; Magnesium Salicylate
          • Cilostazol
          • Citalopram
          • Clofarabine
          • Clopidogrel
          • Collagenase
          • Cytarabine, ARA-C
          • Dasatinib
          • Deferasirox
          • Deoxycholic Acid
          • Desvenlafaxine
          • Dextran
          • Diclofenac
          • Diclofenac; Misoprostol
          • Diflunisal
          • Diphenhydramine; Ibuprofen
          • Diphenhydramine; Naproxen
          • Dipyridamole
          • Duloxetine
          • Eltrombopag
          • Epoprostenol
          • Eptifibatide
          • Escitalopram
          • Esterified Estrogens; Methyltestosterone
          • Etodolac
          • Fenoprofen
          • Fish Oil, Omega-3 Fatty Acids (Dietary Supplements)
          • Fluoxetine
          • Flurbiprofen
          • Fluvoxamine
          • Garlic, Allium sativum
          • Ginger, Zingiber officinale
          • Ginkgo, Ginkgo biloba
          • Green Tea
          • Hydrocodone; Ibuprofen
          • Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate
          • Ibrutinib
          • Ibuprofen
          • Ibuprofen; Famotidine
          • Ibuprofen; Oxycodone
          • Ibuprofen; Pseudoephedrine
          • Icosapent ethyl
          • Iloprost
          • Indomethacin
          • Inotersen
          • Intravenous Lipid Emulsions
          • Ketoprofen
          • Ketorolac
          • Levomilnacipran
          • Lomustine, CCNU
          • Magnesium Salicylate
          • Meclofenamate Sodium
          • Mefenamic Acid
          • Meloxicam
          • Methenamine; Sodium Salicylate
          • Methylsulfonylmethane, MSM
          • Methyltestosterone
          • Milnacipran
          • Miltefosine
          • Mycophenolate
          • Nabumetone
          • Naproxen
          • Naproxen; Esomeprazole
          • Naproxen; Pseudoephedrine
          • Nelarabine
          • Nintedanib
          • Obinutuzumab
          • Olanzapine; Fluoxetine
          • Omidubicel
          • Oxandrolone
          • Oxaprozin
          • Paroxetine
          • Piperacillin; Tazobactam
          • Piroxicam
          • Prasugrel
          • Salsalate
          • Sertraline
          • Sulindac
          • Sumatriptan; Naproxen
          • Telavancin
          • Ticagrelor
          • Tipranavir
          • Tirofiban
          • Tolmetin
          • Trazodone
          • Treprostinil
          • Venlafaxine
          • Verteporfin
          • Vilazodone
          • Vortioxetine

          Level 4 (Minor)

          • Methoxsalen
          Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Acetaminophen; Aspirin: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Acetaminophen; Aspirin; diphenhydrAMINE: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Acetaminophen; 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. [29732] [40621] [49946] 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. [53295] Alteplase: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants. [5199] Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] 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. [29732] [40621] [49946] Anagrelide: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin. [5170] [6912] Apixaban: (Major) Avoid concomitant use of apixaban with antithrombin III 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. [30131] [34885] [52739] Argatroban: (Major) An additive risk of bleeding may be seen in patients receiving argatroban and antithrombin III (AT III) concomitantly. In addition, the half-life of AT III may be altered during concomitant administration with anticoagulants. Coagulation tests (aPTT and anti-Factor Xa, when appropriate) should be performed regularly and especially in the first hours following the start or withdrawal of AT III therapy to ensure appropriate anticoagulation. [29402] [30131] Aspirin, ASA: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Aspirin, ASA; Butalbital; Caffeine: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Aspirin, ASA; Caffeine: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Aspirin, ASA; 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. [5168] [6880] (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Aspirin, ASA; Omeprazole: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Aspirin, ASA; oxyCODONE: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Betrixaban: (Major) Avoid use of betrixaban with antithrombin III 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. [30131] [34885] [62037] Bismuth Subsalicylate: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Bismuth Subsalicylate; metroNIDAZOLE; Tetracycline: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Bivalirudin: (Major) Generally, an additive risk of bleeding may be seen in patients receiving other anticoagulants, including antithrombin III (AT III), in combination with bivalirudin. In clinical trials in patients undergoing PTCA, patients receiving bivalirudin with heparin, warfarin, or thrombolytics had increased risks of major bleeding events compared to those receiving bivalirudin alone. In addition, the half-life of AT III may be altered during concomitant administration with anticoagulants. [29586] [30131] 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. [29732] [40621] [49946] Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] 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. [63940] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] Chlorambucil: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. [4757] [5170] 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. [29732] [40621] [49946] Choline Salicylate; Magnesium Salicylate: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] 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. [5167] [6880] Citalopram: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28260] [28269] [28270] [28343] [32127] [47184] Clofarabine: (Moderate) Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. [5170] [5279] 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. [5164] [6880] 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. [38955] 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. [5208] Dabigatran: (Major) Avoid use of dabigatran with antithrombin III 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. [30131] [34885] [42121] Dalteparin: (Major) As a regulator of hemostasis, antithrombin III (AT III) may increase bleeding risk in patients receiving low molecular weight heparins (LMWHs) concomitantly. The anticoagulant effect of LMWHs is enhanced by concurrent treatment with AT III in patients with hereditary AT III deficiency. In addition, the half-life of AT III may be altered during concomitant administration with anticoagulants. Thus, in order to avoid bleeding, the LMWH dosage may need to be reduced during treatment with AT III. Coagulation tests (aPTT and anti-Factor Xa, when appropriate) should be performed regularly and especially in the first hours following the start or withdrawal of AT III therapy to ensure appropriate anticoagulation. [29732] [30131] [34885] Danazol: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants. [3946] 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. [60087] 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. [31807] 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. [60681] Deoxycholic Acid: (Moderate) Use deoxycholic acid with caution in patients receiving anticoagulants. Excessive bruising or bleeding may occur in and around the treatment area. [59502] Desvenlafaxine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28275] [29934] [34940] [55469] Dextran: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently. [49553] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] 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. [5168] [6880] DULoxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28275] [29934] [34940] [55469] Edoxaban: (Major) Avoid concurrent use of edoxaban with antithrombin III due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if edoxaban and other anticoagulants are used concomitantly. Coadministration of edoxaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with edoxaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from edoxaban. [30131] [34885] [58685] 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. [40392] Enoxaparin: (Major) As a regulator of hemostasis, antithrombin III (AT III) may increase bleeding risk in patients receiving low molecular weight heparins (LMWHs) concomitantly. The anticoagulant effect of LMWHs is enhanced by concurrent treatment with AT III in patients with hereditary AT III deficiency. In addition, the half-life of AT III may be altered during concomitant administration with anticoagulants. Thus, in order to avoid bleeding, the LMWH dosage may need to be reduced during treatment with AT III. Coagulation tests (aPTT and anti-Factor Xa, when appropriate) should be performed regularly and especially in the first hours following the start or withdrawal of AT III therapy to ensure appropriate anticoagulation. [29732] [30131] [34885] Epoprostenol: (Moderate) When used concurrently with anticoagulants, epoprostenol may increase the risk of bleeding. [4892] 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. [6880] [6890] Escitalopram: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28260] [28269] [28270] [28343] [32127] [47184] 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. [29883] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] 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. [26860] [29141] [29579] [30541] FLUoxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28260] [28269] [28270] [28343] [32127] [47184] 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. [29732] [40621] [49946] fluvoxaMINE: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28260] [28269] [28270] [28343] [32127] [47184] Fondaparinux: (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. [30131] [34885] [40227] 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. [25588] [25600] [28470] [28549] [63043] 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. [28470] [28836] [28837] [29137] Ginkgo, Ginkgo biloba: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and antithrombin III 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. [25082] [25083] [25273] [28470] [41251] [41258] [41265] 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. [367] [6434] [6440] [6529] [6581] 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. [6701] [6702] Heparin: (Major) As a regulator of hemostasis, antithrombin III (AT III) may increase bleeding risk in patients receiving heparin concomitantly. The anticoagulant effect of heparin is enhanced by concurrent treatment with AT III in patients with hereditary AT III deficiency. In addition, the half-life of AT III may be altered during concomitant administration with anticoagulants. Thus, in order to avoid bleeding, the heparin dosage may need to be reduced during treatment with AT III. Coagulation tests (aPTT and anti-Factor Xa, when appropriate) should be performed regularly and especially in the first hours following the start or withdrawal of AT III therapy to ensure appropriate anticoagulation. [30131] [34885] 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. [29732] [40621] [49946] Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] 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. [41826] Ibrutinib: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as antithrombin III 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. [56410] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] 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. [3535] [5879] [6320] [7299] Iloprost: (Moderate) When used concurrently with anticoagulants, inhaled iloprost may increase the risk of bleeding. [7537] 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. [29732] [40621] [49946] 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. [63624] 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. [26860] [29141] [29579] [30541] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] Levomilnacipran: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28275] [29934] [34940] [55469] 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. [5170] [5279] [7668] Low Molecular Weight Heparins: (Major) As a regulator of hemostasis, antithrombin III (AT III) may increase bleeding risk in patients receiving low molecular weight heparins (LMWHs) concomitantly. The anticoagulant effect of LMWHs is enhanced by concurrent treatment with AT III in patients with hereditary AT III deficiency. In addition, the half-life of AT III may be altered during concomitant administration with anticoagulants. Thus, in order to avoid bleeding, the LMWH dosage may need to be reduced during treatment with AT III. Coagulation tests (aPTT and anti-Factor Xa, when appropriate) should be performed regularly and especially in the first hours following the start or withdrawal of AT III therapy to ensure appropriate anticoagulation. [29732] [30131] [34885] Magnesium Salicylate: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] Methenamine; Sodium Salicylate: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Methoxsalen: (Minor) Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy. [6625] 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. [32984] [32986] 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. [29883] miFEPRIStone: (Contraindicated) When mifepristone is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the risk of serious bleeding. [28003] [48697] Milnacipran: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28275] [29934] [34940] [55469] 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. [56867] 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. [4873] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. [8493] 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. [58203] 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. [29732] [40621] [49946] 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. [56353] OLANZapine; FLUoxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28260] [28269] [28270] [28343] [32127] [47184] 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. [52213] Omidubicel: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently. [49553] 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. [28549] [47397] 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. [29732] [40621] [49946] PARoxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28260] [28269] [28270] [28343] [32127] [47184] Pentosan: (Major) Pentosan is a weak anticoagulant. Pentosan has 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with pentosan. In a study of healthy subjects who received pentosan 100 mg or placebo every 8 hours for 7 days and received warfarin at a dose to achieve a target INR of 1.4-1.8, the pharmacokinetic parameters of S- and R-warfarin and the INR were similar with and without pentosan. [30131] [40043] 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. [28549] [57681] [57682] [6749] [6750] [8348] 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. [29732] [40621] [49946] 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. [30054] 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. [30054] 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. [36055] [6880] Reteplase, r-PA: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants. [5199] Rivaroxaban: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with antithrombin III; the safety of concomitant use has not been studied. [30131] [34885] [44854] Salicylates: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] Salsalate: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding. [28440] 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 antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28260] [28269] [28270] [28343] [32127] [47184] 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 antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28275] [29934] [34940] [55469] Sertraline: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28260] [28269] [28270] [28343] [32127] [47184] 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. [29732] [40621] [49946] 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. [29732] [40621] [49946] Telavancin: (Moderate) Telavancin has no effect on coagulation or platelet aggregation; however, caution is advised when administering telavancin concurrently with other 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. [36615] Tenecteplase: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants. [5199] Thrombolytic Agents: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants. [5199] Ticagrelor: (Moderate) Theoretically, as a regulator of hemostasis, antithrombin III (AT III) may increase bleeding risk in patients receiving platelet inhibitors (e.g., aspirin, ASA, clopidogrel) concomitantly. Patients should be monitored for appropriate anticoagulation during coadministration of AT III and platelet inhibitors. [6880] 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. [8102] Tirofiban: (Moderate) Concomitant use of tirofiban and other agents that effect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding. [6891] 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. [29732] [40621] [49946] 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. [38831] Treprostinil: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding. [6960] Venlafaxine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. [28275] [29934] [34940] [55469] 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. [30003] 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. [43177] [4996] [5279] Vorapaxar: (Major) Avoid concomitant use of vorapaxar and 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. [57151] 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. [56041] Warfarin: (Major) As a regulator of hemostasis, antithrombin III (AT III) may increase bleeding risk in patients receiving warfarin concomitantly. The half-life of AT III may be altered during concomitant administration with anticoagulants. Patients should be monitored for appropriate anticoagulation during coadministration of AT III and coumarin anticoagulants. [28549] [30131] [34885]
          Revision Date: 11/20/2024, 01:31:00 AM

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          Monitoring Parameters

          • antithrombin III levels

          US Drug Names

          • ATryn
          • Thrombate III
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