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  • CLASSES

    Urinary Analgesics and Anesthetics

    DEA CLASS

    Rx

    DESCRIPTION

    A weak anticoagulant (1/15 the activity of heparin); a semi-synthetic, heparin-like derivative that chemically and structurally resembles glycosaminoglycans; for the relief of pain and discomfort associated with interstitial cystitis.

    COMMON BRAND NAMES

    Elmiron

    HOW SUPPLIED

    Elmiron Oral Cap: 100mg

    DOSAGE & INDICATIONS

    For the relief of bladder pain or discomfort associated with interstitial cystitis.
    Oral dosage
    Adults and Adolescents >= 16 years

    100 mg PO 3 times daily on an empty stomach with water, at least 1 hour before or 2 hours after meals. If pain has not improved after 3 months of therapy and if limiting adverse events have not occurred, pentosan may be continued for an additional 3 months. The clinical benefit of treatment beyond 6 months for patients whose pain has not improved is not known.

    MAXIMUM DOSAGE

    Adults

    300 mg/day PO.

    Geriatric

    300 mg/day PO.

    Adolescents

    >= 16 years: 300 mg/day PO.
    <  16 years: Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. However, pentosan does undergo hepatic metabolism and hepatic impairment may have an effect on the pharmacokinetics of pentosan. Use with caution in patients with hepatic impairment.

    Renal Impairment

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

    ADMINISTRATION

    Oral Administration

    Administer with water on an empty stomach, at least 1 hour before or 2 hours after meals.

    STORAGE

    Elmiron:
    - Store at room temperature (between 59 to 86 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Pentosan is contraindicated in patients with known hypersensitivity to pentosan, structurally related compounds, or excipients.
     
    Pentosan is metabolized, in part, by the spleen. The extent to which splenic disorders may increase pentosan bioavailability is unknown. Therefore, pentosan should be used cautiously in patients with splenic disorders.

    Aneurysm, bleeding, coagulopathy, diverticulitis, hemophilia, inflammatory bowel disease, peptic ulcer disease

    Although the anticoagulant properties of pentosan are very weak (1/15 the activity of heparin), bleeding complications have been reported. Pentosan should be used with caution in patients who have a coagulopathy. Use of pentosan should be carefully evaluated in any patient undergoing an invasive procedure and in any disease state in which there is an increased risk of hemorrhage, such as aneurysm, hemophilia, active inflammatory bowel disease, hemostatic defects secondary to severe hepatic insufficiency, peptic ulcer disease, or diverticulitis.

    Anticoagulant therapy

    Pentosan should be used with caution in patients receiving anticoagulant therapy (e.g., heparin, warfarin), thrombolytic agents (e.g., alteplase, reteplase, streptokinase), or anti-platelet agents (e.g. aspirin, ticlopidine) due to the potential increased risk of bleeding. NSAIDs should also be used cautiously because of their potential to cause GI bleeding.

    Thrombocytopenia

    Pentosan should be used with caution in patients with a history of type II heparin-induced thrombocytopenia (HIT). A product similar to pentosan that was given subcutaneously, sublingually, or intramuscularly (and not initially metabolized by the liver) was associated with immune-mediated (type II) HIT. At least one case of pentosan-induced type II thrombocytopenia has been documented.

    Obstetric delivery, pregnancy

    Pentosan is classified as FDA pregnancy risk category B. No adequate and well controlled studies exist in pregnant women. Use during pregnancy only if clearly needed. Although pentosan's anticoagulant effect is relatively weak compared to other anticoagulants, use caution when administering to a women near the time of obstetric delivery; there may be an increased risk for peripartum bleeding.

    Breast-feeding

    According to the manufacturer, it is not known whether pentosan is excreted in breast milk. Pentosan has a high molecular weight (4000—6000 Daltons) and low oral bioavailability, suggesting that clinically significant exposure would not occur via breast milk. However, the manufacturer recommends caution if administered to a woman who is breast-feeding.

    Children, infants, neonates

    The safe and effective use of pentosan has not been established in neonates, infants, children, or adolescents less than 16 years old.

    Hepatic disease


    NOTE: remove 'hepatic encephalopathy' term (just a place marker) and replace with 'hepatic disease' Pentosan should be used cautiously in patients with hepatic insufficiency. Although pentosan has not been studied in patients with hepatic insufficiency, it is metabolized by the liver, and hepatic disease may have an impact on the pharmacokinetics of pentosan. Mild (<2.5 times normal) elevations in liver function tests have occurred in patients receiving pentosan (see Adverse Reactions). These laboratory abnormalities are usually transient; however, they may remain stable or, rarely, progress with continued use.

    ADVERSE REACTIONS

    Severe

    optic neuritis / Delayed / 0-1.0
    retinal hemorrhage / Delayed / 0-1.0

    Moderate

    elevated hepatic enzymes / Delayed / 1.2-1.2
    esophagitis / Delayed / 0-1.0
    gastritis / Delayed / 0-1.0
    constipation / Delayed / 0-1.0
    colitis / Delayed / 0-1.0
    anemia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    amblyopia / Delayed / 0-1.0
    dyspnea / Early / 0-1.0
    conjunctivitis / Delayed / 0-1.0
    bleeding / Early / Incidence not known
    nystagmus / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    vaginitis / Delayed / Incidence not known

    Mild

    diarrhea / Early / 4.0-4.0
    nausea / Early / 4.0-4.0
    alopecia / Delayed / 4.0-4.0
    rash / Early / 3.0-3.0
    headache / Early / 3.0-3.0
    dyspepsia / Early / 2.0-2.0
    abdominal pain / Early / 2.0-2.0
    ecchymosis / Delayed / 0-1.0
    epistaxis / Delayed / 0-1.0
    anorexia / Delayed / 0-1.0
    flatulence / Early / 0-1.0
    vomiting / Early / 0-1.0
    urticaria / Rapid / 0-1.0
    pruritus / Rapid / 0-1.0
    photosensitivity / Delayed / 0-1.0
    tinnitus / Delayed / 0-1.0
    dizziness / Early / 1.0-1.0
    pharyngitis / Delayed / 0-1.0
    hyperkinesis / Delayed / Incidence not known
    emotional lability / Early / Incidence not known
    insomnia / Early / Incidence not known
    rhinitis / Early / Incidence not known
    lacrimation / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) The use of abciximab within 7 days of use an oral anticoagulant is contraindicated unless the patient's prothrombin time is less than or equal to 1.2 times the control value. Because abciximab inhibits platelet aggregation, additive effects may be seen when abciximab is given in combination with other agents that affect hemostasis such as other platelet inhibitors (e.g. aspirin, ASA, clopidogrel, dipyridamole, ticlopidine), thrombolytic agents (e.g. alteplase, reteplase, streptokinase), and anticoagulants (e.g., heparin, warfarin). However, in clinical trials with abciximab, aspirin and heparin were administered concomitantly. The bleeding risk is significantly increased with concurrent abciximab and thrombolytic therapy; the risks of combination therapy should be weighed against the potential benefits. The GUSTO V study evaluated reduced-dose reteplase in combination with full dose abciximab, in comparison to full dose reteplase alone in patients with acute myocardial infarction (MI); all patients received concurrent aspirin and heparin therapy. The combination regimen was associated with a two-fold increase in moderate to severe non-intracranial bleeding complications, including spontaneous GI bleeding. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Although NSAIDs lacks platelet inhibitory effects, an increased risk for GI bleeding is possible when NSAIDs are administered during abciximab therapy.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Alteplase: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Altretamine: (Moderate) Due to the thrombocytopenic effects of altretamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Antithrombin III: (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.
    Antithymocyte Globulin: (Moderate) Drugs that can cause thrombocytopenia, such as antithymocyte globulin, may lead to an increased risk of bleeding when given concurrently with anticoagulants.
    Apixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. Discontinue apixaban in patients with active bleeding. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding. Pentosan is a weak anticoagulant. Pentosan has one-fifteenth the anticoagulant activity of heparin.
    Argatroban: (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.
    Arsenic Trioxide: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Aspirin, ASA: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Carisoprodol: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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. (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Omeprazole: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Oxycodone: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Pravastatin: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Betrixaban: (Major) Avoid concurrent use of betrixaban with pentosan 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. Pentosan is a weak anticoagulant. Pentosan has one-fifteenth the anticoagulant activity of heparin.
    Bevacizumab: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Bismuth Subsalicylate: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Bivalirudin: (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.
    Carbenicillin: (Moderate) Some penicillins (e.g., carbenicillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Celecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Chlorambucil: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Choline Salicylate; Magnesium Salicylate: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Chondroitin; Glucosamine: (Moderate) Increased effects from concomitant anticoagulant drugs such as increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants such as warfarin until data confirming the safety of MSM in patients taking these drugs are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving warfarin should be observed for increased bleeding.
    Cilostazol: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Clofarabine: (Moderate) Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Clopidogrel: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants.
    Cod Liver Oil: (Major) Cod liver oil should be used only with caution and with frequent monitoring in patients on concurrent anticoagulants. In a limited number of patients, the hypoprothrombinemic response to warfarin was increased following large doses of vitamin A. Additionally, omega-3 fatty acids contained in cod liver oil may inhibit platelet aggregation. Theoretically, the risk of bleeding may be increased, but some studies that combined omega-3 fatty acids and anticoagulant agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3 to 6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant cod liver oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly. (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Cytarabine, ARA-C: (Moderate) Due to the thrombocytopenic effects of pyrimidine analogs, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Dabigatran: (Major) Pentosan is a weak anticoagulant. Pentosan has 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in patients receiving other anticoagulants (e.g., dabigatran) in combination with pentosan.
    Dalteparin: (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.
    Danaparoid: (Severe) 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.
    Danazol: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Dasatinib: (Moderate) Monitor for evidence of bleeding if coadministration of dasatinib and anticoagulants is necessary. Dasatinib can cause serious and fatal bleeding. Concomitant anticoagulants may increase the risk of hemorrhage.
    Decitabine: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Deferasirox: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Defibrotide: (Severe) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
    Denileukin Diftitox: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Desirudin: (Major) Pentosan is a weak anticoagulant. Pentosan has 1/15 the anticoagulant activity of heparin. Any agent which may enhance the risk of hemorrhage should generally be discontinued before initiating desirudin therapy. An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with pentosan. If coadministration cannot be avoided, close clinical and laboratory monitoring should be conducted.
    Desvenlafaxine: (Major) Platelet aggregation may be impaired by desvenlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Dextran: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
    Diclofenac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diclofenac; Misoprostol: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diflunisal: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diphenhydramine; Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diphenhydramine; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Dipyridamole: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any anticoagulants. There is an additive risk of beeding.
    Duloxetine: (Major) Platelet aggregation may be impaired by duloxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Edoxaban: (Major) Avoid concurrent use of edoxaban with pentosan 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. Pentosan is a weak anticoagulant. Pentosan has one-fifteenth the anticoagulant activity of heparin.
    Eltrombopag: (Moderate) Use caution when discontinuing eltrombopag in patients receiving anticoagulants (e.g., warfarin, enoxaparin, dabigatran, rivaroxaban). The risk of bleeding and recurrent thrombocytopenia is increased in patients receiving these drugs when eltrombopag is discontinued.
    Enoxaparin: (Major) 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. Monitor clinical and laboratory response closely when enoxaparin is coadministered with drugs known to increase the risk of bleeding.
    Epoprostenol: (Moderate) When used concurrently with anticoagulants, epoprostenol may increase the risk of bleeding.
    Eptifibatide: (Moderate) Concomitant use of eptifibatide and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
    Esomeprazole; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Esterified Estrogens; Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
    Estramustine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Etodolac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Famotidine; Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fenoprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Floxuridine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Fluorouracil, 5-FU: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Flurbiprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Fondaparinux: (Major) Discontinue pentosan before starting fondaparinux due to the increased bleeding risk, unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding. Pentosan is a weak anticoagulant. Pentosan has one-fifteenth the anticoagulant activity of heparin.
    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.
    Gefitinib: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Ginger, Zingiber officinale: (Moderate) Additive bleeding may occur if anticoagulants are given in combination with ginger, zingiber officinale. Ginger inhibits thromboxane synthetase (platelet aggregation inducer) and is a prostacyclin agonist. Patients taking ginger and an anticoagulant should be monitored closely for bleeding.
    Ginkgo, Ginkgo biloba: (Major) Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants. Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants (e.g., warfarin), aspirin, ASA or other platelet inhibitors, or thrombolytic agents. A patient who had been taking aspirin 325 mg/day PO for 3 years following coronary-artery bypass surgery, developed spontaneous bleeding into his eye after taking a standardized extract of Ginkgo biloba (Ginkoba commercial product) 40 mg PO twice daily for one week. The patient stopped taking the ginkgo but continued taking the aspirin with no recurrence of bleeding over a 3-month period. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic ginkgo biloba ingestion.
    Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if co-administered with anticoagulants (e.g., enoxaparin, heparin, warfarin, and others) thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, cilostazol and others). Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with any of these agents. Exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin; stability of the diet can be an important factor in maintaining anticoagulation goals. Occult sources of vitamin K include green tea and green tea dietary supplements. Published data are limited in regard to this interaction. A patient with previous INRs of 3.2. and 3.79 on a dose of 7.5mg daily of warfarin (goal INR 2.5 to 3.5) had an INR of 1.37. One month later, the patient's INR was 1.14. The patient admitted that he had started consuming 0.51 gallon of green tea daily approximately one week prior to the INR of 1.37. The patient denied noncompliance and other changes in diet, medications, or health. The patient discontinued green tea and one week later his INR was 2.55. While the amount of vitamin K in a single cup of brewed green tea may not be high (0.03 mcg/100 g), the actual amount may vary from cup to cup depending on the amount of tea leaves used, the length of time the tea bags are allowed to brew, and the volume of tea consumed. Additionally, if a patient drinks multiple cups of tea per day, the amount of vitamin K could reach significance. It is recommended that patients on warfarin maintain a stable intake of green tea.
    Guarana: (Major) Guarana has been shown to possess minor antiplatelet activity and, therefore, concurrent use of guarana and anticoagulants or platelet inhibitors should be avoided.
    Hemin: (Major) Because hemin has exhibited transient, mild anticoagulant effects during clinical studies, concurrent use of anticoagulants should be avoided. The extent and duration of the hypocoagulable state induced by hemin has not been established.
    Heparin: (Major) Pentosan is a weak anticoagulant. Pentosan has 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in patients receiving other anticoagulants (e.g., heparin, warfarin) in combination with pentosan.
    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.
    Hydroxyurea: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with coagulation such as anticoagulants; the risk of bleeding may be increased. If coadministration with anticoagulants is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
    Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Oxycodone: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Pseudoephedrine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Iloprost: (Moderate) When used concurrently with anticoagulants, inhaled iloprost may increase the risk of bleeding.
    Imatinib: (Major) Pentosan is a weak anticoagulant. Pentosan has 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with pentosan.
    Indomethacin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
    Interferon Alfa-2a: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b; Ribavirin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfacon-1: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-n3: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Intravenous Lipid Emulsions: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Kava Kava, Piper methysticum: (Moderate) Kava kava, Piper methysticum does appear to have some anti-thrombotic activity. Persons who are receiving anticoagulants should not take kava kava without first discussing use with their health care professional. Kava kava, Piper methysticum exhibits antithrombotic activity and also inhibits CYP isozymes important in warfarin clearance such as CYP2C9, 2C19, 1A2 and 3A4. Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.
    Ketoprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ketorolac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Lansoprazole; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Lepirudin: (Major) 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.
    Levomilnacipran: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Lomustine, CCNU: (Moderate) Due to the bone marrow suppressive and thrombocytopenic effects of lomustine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Magnesium Salicylate: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meclofenamate Sodium: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Mefenamic Acid: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Meloxicam: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Methoxsalen: (Minor) Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs such as increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants such as warfarin until data confirming the safety of MSM in patients taking these drugs are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving warfarin should be observed for increased bleeding.
    Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
    Mifepristone: (Major) When mifepristone is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the increased risk of serious bleeding. When mifepristone is used chronically for hormonal conditions, such as Cushing's disease, the concurrent use of some anticoagulants should be approached with caution, but specific interactions with pentosan are not expected.
    Milnacipran: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Miltefosine: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
    Mycophenolate: (Moderate) Mycophenolate may causes thrombocytopenia and increase the risk for bleeding. Agents which may lead to an increased incidence of bleeding in patients with thrombocytopenia include anticoagulants.
    Nabumetone: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Nandrolone Decanoate: (Moderate) Androgens can enhance the effects of anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain prothrombin time at the desired therapeutic level. When anabolic steroid or androgen therapy is started or stopped in patients on anticoagulant therapy, close monitoring is required. Additionally, nandrolone decanoate may generate a pharmacodynamic interaction with warfarin by independently affecting the activity of circulating coagulation proteins. Androgens reduce the amount or activity of circulating coagulant proteins thereby enhancing the anticoagulant effect of warfarin.
    Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Pseudoephedrine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Sumatriptan: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Natural Antineoplastics: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Nintedanib: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Nonsteroidal antiinflammatory drugs: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Omacetaxine: (Major) Avoid the concomitant use of omacetaxine and anticoagulants when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Oxandrolone: (Moderate) An increased effect of anticoagulants may occur with oxandrolone; the anticoagulant dosage may need adjustment downward with oxandrolone initiation or adjustment upward with oxandrolone discontinuation to maintain the desired clinical effect. Oxandrolone suppresses clotting factors II, V, VII, and X, which results in an increased prothrombin time. An increase in plasminogen-activator activity, and serum concentrations of plasminogen, protein C, and antithrombin III have occurred with several 17-alpha-alkylated androgens. For example, concurrent use of oxandrolone and warfarin may result in unexpectedly large increases in the INR or prothrombin time (PT). A multidose study of oxandrolone (5 or 10 mg PO twice daily) in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80 to 85% dose reduction) was necessary to maintain a target INR of 1.5. According to the manufacturer, if oxandrolone therapy is initiated in a patient already receiving warfarin, the dose of warfarin may need to be decreased significantly to reduce the potential for excessive INR elevations and associated risk of serious bleeding events. The patient should be closely monitored with frequent evaluation of the INR and clinical parameter, and the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen therapy is changed or discontinued.
    Oxaprozin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Photosensitizing agents: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Piperacillin: (Moderate) Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Piperacillin; Tazobactam: (Moderate) Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Piroxicam: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Porfimer: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone (DHEA) is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone (DHEA) is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasugrel: (Moderate) Concomitant use of prasugrel and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
    Reteplase, r-PA: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Rivaroxaban: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with pentosan. Pentosan is a weak anticoagulant. Pentosan has one-fifteenth the anticoagulant activity of heparin.
    Rofecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Salicylates: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Salsalate: (Moderate) 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 platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Selective serotonin reuptake inhibitors: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants, like pentosan. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Sodium Hyaluronate, Hyaluronic Acid: (Moderate) Increased bruising or bleeding at the injection site may occur when using hyaluronate sodium with anticoagulants, including pentosan, especially if used within the 3 weeks prior to the procedure.
    Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
    Streptokinase: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Sulfinpyrazone: (Major) Sulfinpyrazone should be avoided when possible with concurrent anticoagulants, thrombin inhibitors, and thrombolytic agents due to potential for increased bleeding risk. Alternative uricosuric agents may be considered. Sulfinpyrazone is a platelet inhibitor and exhibits antithrombotic actions in addition to its uricosuric effects. Additive hematological effects are possible as a result of the platelet inhibitory effects of sulfinpyrazone; the sulfide metabolite of sulfinpyrazone appears responsible for this effect. Sulfinpyrazone is also known to markedly potentiate the effect of warfarin. Sulfinpyrazone may inhibit CYP2C9, leading to a decrease in the clearance of S-warfarin. If concurrent therapy is warranted, significant initial dosage reductions (e.g., 50%) of warfarin may be necessary, with further dosage adjusted based on INR values. The INR should be closely monitored during concurrent therapy with warfarin, particularly during the initiation or termination phases of sulfinpyrazone treatment.
    Sulindac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Telavancin: (Moderate) Telavancin has no effect on coagulation or platelet aggregation; however, caution is advised when administering telavancin concurrently with anticoagulants as telavancin may interfere with laboratory tests used in monitoring these medications. The coagulation tests affected by telavancin include prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), activated clotting time, and coagulation based factor Xa tests. When measured shortly after completion of a telavancin infusion, the results of these tests are increased; however, the effects of telavancin on these tests dissipate over time as plasma concentrations of telavancin decrease. Therefore, when administering telavancin in conjunction with anticoagulants ensure that blood samples for these coagulation tests are collected as close as possible to the patient's next telavancin dose.
    Tenecteplase: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Thrombolytic Agents: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Ticagrelor: (Moderate) 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 platelet inhibitors in combination with pentosan.
    Ticarcillin: (Moderate) Some penicillins (e.g., ticarcillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Ticarcillin; Clavulanic Acid: (Moderate) Some penicillins (e.g., ticarcillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Ticlopidine: (Moderate) Because ticlopidine inhibits platelet aggregation, a potential additive risk for bleeding exists if ticlopidine is given in combination with other agents that affect hemostasis such as anticoagulants. Per the manufacturer of ticlopidine, if a patient is switched from an anticoagulant or a thrombolytic agent to ticlopidine, the former drug should be discontinued prior to the administration of ticlopidine.
    Tinzaparin: (Major) 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 tinzaparin in combination with pentosan.
    Tipranavir: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including anticoagulants, that may have caused or contributed to these events.
    Tirofiban: (Moderate) Concomitant use of tirofiban and other agents that effect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
    Tolmetin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Trazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on anticoagulant therapy.
    Treprostinil: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
    Tretinoin, ATRA: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Urokinase: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Valdecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Venlafaxine: (Major) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Verteporfin: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. In addition, both vilazodone and warfarin are highly protein bound, which may result in displacement of warfarin from protein binding sites and an increased anticoagulant effect. It would be prudent for clinicians to monitor the INR and clinical status of the patient closely if vilazodone is added to or removed from the regimen of a patient stabilized on warfarin.
    Vorapaxar: (Major) Pentosan is a weak anticoagulant with 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in patients receiving other platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Vorinostat: (Moderate) Concomitant use of vorinostat with anticoagulants, including the weak anticoagulant pentosan, may result in an additive risk of bleeding due to vorinostat-induced thrombocytopenia; monitor patients closely.
    Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Co-administration of vortioxetine and warfarin has not been shown to significantly affect the pharmacokinetics of either agent.
    Warfarin: (Major) 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 warfarin 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.

    PREGNANCY AND LACTATION

    Pregnancy

    Pentosan is classified as FDA pregnancy risk category B. No adequate and well controlled studies exist in pregnant women. Use during pregnancy only if clearly needed. Although pentosan's anticoagulant effect is relatively weak compared to other anticoagulants, use caution when administering to a women near the time of obstetric delivery; there may be an increased risk for peripartum bleeding.

    MECHANISM OF ACTION

    Pentosan is a low molecular weight heparin-like compound with anticoagulant and fibrinolytic effects. It also inhibits the generation of factor Xa in plasma and inhibits thrombin-induced platelet aggregation ex vivo. The mechanism of action of pentosan for relief of pain and discomfort in interstitial cystitis (IC) is unknown. Patients with IC have abnormal epithelial permeability of the bladder wall. It is believed that pentosan may coat the bladder wall and act as a buffer to control epithelial cell permeability, thereby preventing urine from causing further irritation to the bladder wall. Pentosan is also an inhibitor of basic-fibroblast growth factor and is being evaluated for its antitumor activity in AIDS-related Kaposi's sarcoma and other malignancies.

    PHARMACOKINETICS

    Pentosan is administered orally. Pentosan distributes to the uroepithelium of the genitourinary tract, with lesser amounts found in liver, spleen, lung, skin, periosteum, and bone marrow. Pentosan is metabolized by partial desulfation in the liver and spleen and by partial depolymerization in the kidney; both of these processes can be saturated with continued dosing. The majority of an oral dose is excreted in the feces as unchanged drug. About 6% is excreted in urine as desulfated or depolymerized metabolites. The mean half-life of pentosan is 27 hours after administration of a 300 mg dose of radiolabeled oral pentosan and 20 hours after a 450 mg dose.

    Oral Route

    Based on radiolabeled studies, approximately 6% of an oral dose is absorbed and reaches systemic circulation. The effect of food on absorption is unknown. Median peak plasma radioactivity was seen approximately 2 hours (range 0.6—120 hours) after an oral dose when administered under fasted conditions.