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    Pyrimidine Analogs

    BOXED WARNING

    Bone marrow suppression, herpes infection, infection, leukopenia, neutropenia, radiation therapy, requires a specialized care setting, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Floxuridine administration requires an experienced clinician in cancer chemotherapy and intra-arterial therapy who is well versed in the use of potent antimetabolites due to the possibility of severe toxic reactions. Furthermore, because of the risk of severe toxicity, administration requires a specialized care setting and patients should be hospitalized for their first course of therapy. Severe hematological toxicity including bone marrow suppression can occur. Floxuridine should be used cautiously in patients who have had previous myelosuppressive therapy such as chemotherapy or radiation therapy. Severe bone marrow suppression is a contraindication; avoid use in patients with neutropenia and thrombocytopenia. Closely monitor hematologic status during treatment. Patients with a pretreatment leukopenia (WBC < 2000/mm3) or thrombocytopenia (platelet count < 100,000/mm3) are at risk of additional bone marrow suppression. Discontinue treatment at the first visible sign of leukopenia (WBC < 3500/mm3), a rapidly falling white blood count, or thrombocytopenia. Treat any active infection before initiating floxuridine and discontinue treatment or reduce the dose upon development of an infection. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection during treatment.

    DEA CLASS

    Rx

    DESCRIPTION

    Fluorinated pyrimidine antimetabolite antineoplastic agent; deoxyribonucleoside derivative of 5-FU; used almost exclusively via hepatic artery administration for colon cancer metastatic to the liver; preferred over 5-FU for intrahepatic administration. FUDR(R) brand is no longer available, however generic formulations have been FDA-approved.

    COMMON BRAND NAMES

    FUDR

    HOW SUPPLIED

    Floxuridine/FUDR Intra-Arterial Inj Pwd F/Sol: 500mg

    DOSAGE & INDICATIONS

    For the treatment of colorectal cancer metastatic to the liver.
    Intra-arterial dosage
    Adults

    0.1—0.6 mg/kg/day as a continuous intra-arterial infusion into the hepatic artery.

    For the treatment of unresectable hepatocellular cancer†, in combination with radiotherapy.
    Intra-arterial dosage
    Adults

    0.2 mg/kg/day via a percutaneous brachial or hepatic arterial catheter as a continuous infusion concurrently with radiation therapy (RT) has been studied; RT consisted of two 2-week blocks (1.5 Gy twice daily Monday thru Friday and once on Saturday) separated by a 2 week break followed by additional RT (median total dose of 60.75 Gy). In a phase II study of 128 patients with unresectable intrahepatic primary hepatobiliary cancers or liver metastases from colorectal cancer who were ineligible for resection or ablation, the overall response rate in the 35 patients with HCC was 40%. Additionally, patients with HCC had a median overall survival (OS) time of 15.2 months, which compared favorably with a historical control estimate of a median OS time of 8 months (p < 0.0001). One patient in this study died as a result of radiation-induced liver disease.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    0.6 mg/kg/day continuous intra-arterial infusion.

    Elderly

    0.6 mg/kg/day continuous intra-arterial infusion.

    Adolescents

    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.

    Renal Impairment

    Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available.

    ADMINISTRATION

     
     
    NOTE: The correct dose of floxuridine will vary from protocol to protocol. Clinicians should consult the appropriate references to verify the dose.
     
    CAUTION: Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs.

    Injectable Administration

    Floxuridine is given parenterally, usually via intrahepatic infusions.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Reconstitution
    Reconstitute 500 mg with 5 mL of sterile water for injection to give a concentration of 100 mg/mL. Dilute calculated daily dose in a sufficient volume of 5% Dextrose injection or 0.9% Sodium Chloride injection.

    Other Injectable Administration

    Intra-arterial infusion
    Infuse floxuridine by continuous intra-arterial infusion via a catheter inserted into the arterial blood supply of the tumor. An infusion pump may be used to overcome pressure in large arteries and to ensure a uniform infusion rate.

    STORAGE

    FUDR:
    - Store reconstituted product in refrigerator (36 to 46 degrees F), discard after 14 days
    - Store unreconstituted product at 68 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Bone marrow suppression, herpes infection, infection, leukopenia, neutropenia, radiation therapy, requires a specialized care setting, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Floxuridine administration requires an experienced clinician in cancer chemotherapy and intra-arterial therapy who is well versed in the use of potent antimetabolites due to the possibility of severe toxic reactions. Furthermore, because of the risk of severe toxicity, administration requires a specialized care setting and patients should be hospitalized for their first course of therapy. Severe hematological toxicity including bone marrow suppression can occur. Floxuridine should be used cautiously in patients who have had previous myelosuppressive therapy such as chemotherapy or radiation therapy. Severe bone marrow suppression is a contraindication; avoid use in patients with neutropenia and thrombocytopenia. Closely monitor hematologic status during treatment. Patients with a pretreatment leukopenia (WBC < 2000/mm3) or thrombocytopenia (platelet count < 100,000/mm3) are at risk of additional bone marrow suppression. Discontinue treatment at the first visible sign of leukopenia (WBC < 3500/mm3), a rapidly falling white blood count, or thrombocytopenia. Treat any active infection before initiating floxuridine and discontinue treatment or reduce the dose upon development of an infection. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection during treatment.

    Dental disease, dental work

    Myelosuppressive effects of floxuridine can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

    Intramuscular injections

    Intramuscular injections should not be administered to patients with platelet counts < 50,000/mm3 who are receiving floxuridine. IM injections may cause bleeding, bruising, or hematomas due to floxuridine-induced thrombocytopenia.

    Pregnancy

    Floxuridine is classified as FDA pregnancy risk category D. It has been shown to cause teratogenic effects in animals at doses 4.2—125 times the recommended human dose, but adequate and well-controlled studies in pregnant women have not been performed. Malformations in animals included cleft palates, skeletal defects, and deformed appendages. Floxuridine should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk. Females of childbearing age should be advised to avoid becoming pregnant while receiving the drug due to the potential risk to the fetus. If a woman becomes pregnant while receiving floxuridine therapy, she should be apprised of the potential risk to the fetus.

    Breast-feeding

    It is uncertain if floxuridine is distributed into breast milk. According to the manufacturer, because of the inhibition of DNA and RNA synthesis by floxuridine, breast-feeding should be discontinued during floxuridine therapy.

    Hepatic disease, hepatitis

    Patients with hepatic disease may have decreased detoxification of floxuridine. Lower dosage regimens may be necessary with hepatic impairment. Floxuridine should be used with caution in patients with a history of hepatitis, because there is an increased risk of chemical hepatitis.

    Renal impairment

    Patients with renal impairment may have decreased floxuridine elimination. Drug accumulation and potential toxicity may occur. Dosage adjustments may be necessary.

    Dihydropyrimidine dehydrogenase (DPD) deficiency

    Certain families have dihydropyrimidine dehydrogenase (DPD) deficiency (familial pyrimidinemia), DPD is an enzyme necessary for degrading fluorouracil (and therefore floxuridine) to an inactive compound. Administration of floxuridine or fluorouracil to these individuals can lead to enhanced neurotoxicity.

    GI bleeding, malnutrition, stomatitis

    Severe GI bleeding may occur during treatment with floxuridine. Use is contraindicated in patients with malnutrition. Discontinue treatment if esophagopharyngitis, vomiting, intractable diarrhea, frequent bowel movements, gastrointestinal ulceration or GI bleeding occurs. Floxuridine can cause serious stomatitis; it should not be given to anyone with preexisting stomatitis to avoid worsening and it should be discontinued if stomatitis does occur.

    Accidental exposure, ocular exposure

    Use care to avoid accidental exposure to floxuridine during preparation, handling, and administration. The use of protective gowns, gloves and goggles is recommended. Following skin or ocular exposure, skin and eyes should be thoroughly rinsed.

    Vaccination

    Vaccination during chemotherapy or radiation therapy (such as floxuridine) should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    ADVERSE REACTIONS

    Severe

    hepatic necrosis / Delayed / Incidence not known
    cholecystitis / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    acute cerebellar syndrome / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    visual impairment / Early / Incidence not known
    thrombosis / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 10.0
    hyperbilirubinemia / Delayed / 10.0
    stomatitis / Delayed / 10.0
    leukopenia / Delayed / 10.0
    anemia / Delayed / 10.0
    thrombocytopenia / Delayed / 10.0
    erythema / Early / 10.0
    glossitis / Early / Incidence not known
    gastritis / Delayed / Incidence not known
    confusion / Early / Incidence not known
    euphoria / Early / Incidence not known
    nystagmus / Delayed / Incidence not known
    angina / Early / Incidence not known
    photophobia / Early / Incidence not known
    phlebitis / Rapid / Incidence not known

    Mild

    diarrhea / Early / 10.0
    nausea / Early / 10.0
    vomiting / Early / 10.0
    anorexia / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    rash / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    xerosis / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    headache / Early / Incidence not known
    lacrimation / Early / Incidence not known
    weakness / Early / Incidence not known
    malaise / Early / Incidence not known
    lethargy / Early / Incidence not known
    infection / Delayed / Incidence not known
    fever / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Allopurinol: (Minor) Allopurinol can interfere in the activation of fluorouracil, 5-FU, and thus impair its activity. Because floxuridine is metabolized to fluorouracil, a similar interaction can occur with floxuridine. Theoretically, this may provide protection to host tissues and preserve anti-tumor activity since host tissues, but not all tumors, rely on the effected activation pathway. However, the reduction of 5-FU toxicity, specifically mucositis, by allopurinol has been inconsistent in clinical trials. In some animal models, allopurinol has decreased the effectiveness of 5-FU.
    Anticoagulants: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Antithrombin III: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Apixaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Argatroban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Betrixaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Minor) Enhancement of toxicity of fluorouracil, 5-FU, has been reported in a limited number of patients during concurrent treatment with metronidazole. This toxicity occurred without an increase in efficacy of fluorouracil. Toxicity may manifest as granulocytopenia, oral ulceration, anemia, and nausea and vomiting. This interaction is believed to occur through reduced clearance of fluorouracil. Floxuridine is a deoxyribonucleoside derivative of fluorouracil and may interact with metronidazole in a similar manner.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Enhancement of toxicity of fluorouracil, 5-FU, has been reported in a limited number of patients during concurrent treatment with metronidazole. This toxicity occurred without an increase in efficacy of fluorouracil. Toxicity may manifest as granulocytopenia, oral ulceration, anemia, and nausea and vomiting. This interaction is believed to occur through reduced clearance of fluorouracil. Floxuridine is a deoxyribonucleoside derivative of fluorouracil and may interact with metronidazole in a similar manner.
    Bivalirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Celecoxib: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Cimetidine: (Minor) Data suggest chronic administration of cimetidine with fluorouracil, 5-FU, can increase 5-FU serum concentrations, but it is not clear if this interaction results in increased 5-FU efficacy or toxicity. Patients receiving either 5-FU or floxuridine should be monitored for a possible increased response to 5-FU if cimetidine is used concurrently.
    Dabigatran: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Dalteparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Danaparoid: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Desirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Diclofenac: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diclofenac; Misoprostol: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diflunisal: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diphenhydramine; Ibuprofen: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diphenhydramine; Naproxen: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with 5-FU may potentiate the adverse effects associated with 5-FU. Since floxuridine is metabolized to 5-FU, a similar interaction may occur with concomitant administration of floxuridine and L-methylfolate.
    Edoxaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Enoxaparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Esomeprazole; Naproxen: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with 5-FU may potentiate the adverse effects associated with 5-FU. Since floxuridine is metabolized to 5-FU, a similar interaction may occur with concomitant administration of floxuridine and L-methylfolate.
    Etodolac: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Famotidine; Ibuprofen: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Fenoprofen: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Flurbiprofen: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Fondaparinux: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Fosphenytoin: (Major) Alterations in phenytoin serum concentrations (increases and decreases) have been reported in patients previously stabilized on phenytoin who receive systemic fluorouracil, 5-FU, chemotherapy. The possibility exists for similar interactions with floxuridine, which is metabolized to 5-FU. Most commonly, decreased phenytoin serum concentrations are reported in the literature, usually associated with decreased phenytoin absorption due to 5-FU induced GI toxicity. However, increased levels of phenytoin have been reported in a small number of patients possibly due to 5-FU inhibition of cytochrome P450 isoenzyme 2C9, which is responsible for phenytoin metabolism.
    Heparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Hydrocodone; Ibuprofen: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Hydroxyurea: (Minor) Neurotoxicity may occur to a significant extent during concomitant administration of floxuridine and hydroxyurea.
    Ibuprofen: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Oxycodone: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Indomethacin: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketoprofen: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketorolac: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lansoprazole; Naproxen: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lepirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Lesinurad; Allopurinol: (Minor) Allopurinol can interfere in the activation of fluorouracil, 5-FU, and thus impair its activity. Because floxuridine is metabolized to fluorouracil, a similar interaction can occur with floxuridine. Theoretically, this may provide protection to host tissues and preserve anti-tumor activity since host tissues, but not all tumors, rely on the effected activation pathway. However, the reduction of 5-FU toxicity, specifically mucositis, by allopurinol has been inconsistent in clinical trials. In some animal models, allopurinol has decreased the effectiveness of 5-FU.
    Leucovorin: (Major) Calcium leucovorin provides reduced folates, which enhance binding of fluorouracil to thymidylate synthetase. This increases both the therapeutic efficacy and the toxicity of fluorouracil. In particular, patients can experience increased diarrhea and stomatitis. Floxuridine is metabolized to fluorouracil, so a similar interaction can occur.
    Levoleucovorin: (Major) Calcium leucovorin provides reduced folates, which enhance binding of fluorouracil to thymidylate synthetase. This increases both the therapeutic efficacy and the toxicity of fluorouracil. In particular, patients can experience increased diarrhea and stomatitis. Floxuridine is metabolized to fluorouracil, so a similar interaction can occur.
    Levomefolate: (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with 5-FU may potentiate the adverse effects associated with 5-FU. Since floxuridine is metabolized to 5-FU, a similar interaction may occur with concomitant administration of floxuridine and L-methylfolate.
    Live Vaccines: (Severe) Do not administer live vaccines to floxuridine recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving floxuridine. At least 2 weeks before initiation of floxuridine therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Floxuridine recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Meclofenamate Sodium: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mefenamic Acid: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meloxicam: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Methotrexate: (Minor) Methotrexate given 3 to 24 hours before 5-FU increases the formation of fluorouridine triphosphate and enhances cell kill and toxicity. When 5-FU is given within 24 hours prior to methotrexate, the cytotoxicity of methotrexate is decreased. Floxuridine is metabolized to 5-FU. Like 5-FU, the scheduling of floxuridine and methotrexate when used together is critical. It appears that the more favorable sequence is administering methotrexate prior to 5-FU due to increased RNA toxicity of 5-FU.
    Metronidazole: (Minor) Enhancement of toxicity of fluorouracil, 5-FU, has been reported in a limited number of patients during concurrent treatment with metronidazole. This toxicity occurred without an increase in efficacy of fluorouracil. Toxicity may manifest as granulocytopenia, oral ulceration, anemia, and nausea and vomiting. This interaction is believed to occur through reduced clearance of fluorouracil. Floxuridine is a deoxyribonucleoside derivative of fluorouracil and may interact with metronidazole in a similar manner.
    Nabumetone: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Sumatriptan: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nonsteroidal antiinflammatory drugs: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Oxaprozin: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentosan: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with floxuridine. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
    Phenytoin: (Major) Alterations in phenytoin serum concentrations (increases and decreases) have been reported in patients previously stabilized on phenytoin who receive systemic fluorouracil, 5-FU, chemotherapy. The possibility exists for similar interactions with floxuridine, which is metabolized to 5-FU. Most commonly, decreased phenytoin serum concentrations are reported in the literature, usually associated with decreased phenytoin absorption due to 5-FU induced GI toxicity. However, increased levels of phenytoin have been reported in a small number of patients possibly due to 5-FU inhibition of cytochrome P450 isoenzyme 2C9, which is responsible for phenytoin metabolism.
    Piroxicam: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and floxuridine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Rivaroxaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Rofecoxib: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Sulindac: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tinzaparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Tolmetin: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Valdecoxib: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Warfarin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.

    PREGNANCY AND LACTATION

    Pregnancy

    Floxuridine is classified as FDA pregnancy risk category D. It has been shown to cause teratogenic effects in animals at doses 4.2—125 times the recommended human dose, but adequate and well-controlled studies in pregnant women have not been performed. Malformations in animals included cleft palates, skeletal defects, and deformed appendages. Floxuridine should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk. Females of childbearing age should be advised to avoid becoming pregnant while receiving the drug due to the potential risk to the fetus. If a woman becomes pregnant while receiving floxuridine therapy, she should be apprised of the potential risk to the fetus.

    It is uncertain if floxuridine is distributed into breast milk. According to the manufacturer, because of the inhibition of DNA and RNA synthesis by floxuridine, breast-feeding should be discontinued during floxuridine therapy.

    MECHANISM OF ACTION

    Floxuridine acts as an antimetabolite. It is a cell cycle-phase specific agent that is most active during the S-phase of the cell cycle. Following continuous intra-arterial infusion, floxuridine is converted to 5-fluorodeoxyuridine-5'-monophosphate (FdUMP) by thymidine kinase. FdUMP forms a tight but reversible covalent bond with thymidylate synthase (TS) in the presence of methylenetetrahydrofolate (CH2-THF), one of the intracellular metabolites of folinic acid. This binding inhibits the formation of thymidylate from uracil. Thymidylate is the necessary precursor of thymidine triphosphate (dTTP), one of four deoxyribonucleotides required for synthesis of DNA. Thus, a deficiency of thymidylate leads to depletion of dTTP, which inhibits cell division. When combined with folinic acid (leucovorin), the antitumor effects are enhanced through stabilization of the ternary complex of TS, FdUMP, and CH2-THF. When floxuridine is given by rapid (rather than continuous) intra-arterial injection, it is catabolized to 5-fluorouracil (5-FU). Thus, rapid injection produces the same toxic and antimetabolic effects as 5-FU. Fluorouracil undergoes conversion to 5-fluorouridine-5'-triphosphate (FUTP) and FdUMP. Nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during synthesis of RNA. Thus, RNA processing and protein synthesis are disrupted.

    PHARMACOKINETICS

    Floxuridine is administered by continuous intra-arterial IV infusion via a hepatic artery catheter. When it is given by rapid (rather than continuous) intra-arterial injection, it is catabolized to 5-fluorouracil (5-FU). Floxuridine and its metabolites distribute widely throughout the body tissues and cross the blood-brain barrier to a significant degree. CSF concentrations can be sustained for several hours. Fluorouracil distributes well into ascites and pleural effusions. Delayed elimination from these fluid reservoirs could prolong toxicity. A small portion is converted to an active metabolite in the tissues, while the rest (80%) is degraded in the liver. A portion of the dose is eliminated by the lungs as carbon dioxide, and the rest (60—90%) is excreted in the urine as metabolites.
     
    Affected cytochrome P450 isoenzymes: CYP2C9
    Drug interactions with fluorouracil should be considered when using floxuridine; fluorouracil is an inhibitor of CYP2C9, though the inhibition appears to be greater following higher doses.