Floxuridine is a cell cycle-phase specific antineoplastic agent used almost exclusively via hepatic artery administration to treat colon carcinoma metastatic to the liver. Floxuridine is a deoxyribonucleoside derivative of fluorouracil (5-FU). Floxuridine is preferred over 5-FU for intrahepatic administration because a greater percentage of floxuridine is removed from the systemic circulation with one pass through the liver, potentially limiting systemic toxicity. Floxuridine is a fluorinated pyrimidine and acts as an antimetabolite, but its mechanism of action is distinct from the other antimetabolites such as methotrexate, cytarabine, mercaptopurine, or thioguanine. Floxuridine was given FDA approval in 1970. In January 2000, the manufacturer of FUDR(R) announced that sterile floxuridine was no longer available. Generic formulations of floxuridine have subsequently been approved.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
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.
Laboratory abnormalities that have been reported in patients who received arterial infusions of floxuridine include BSP, prothrombin, total proteins, sedimentation rate and thrombopenia.
Elevated hepatic enzymes (e.g., increased alkaline phosphatase, transaminase, and lactate dehydrogenase levels) and hyperbilirubinemia have been reported commonly in patients who received arterial infusions of floxuridine. Other toxicity that has been reported with floxuridine use includes possible intra- and extrahepatic biliary sclerosis, hepatic necrosis, and acalculous cholecystitis.
Common gastrointestinal (GI) adverse reactions that have been reported with an arterial infusion of floxuridine include nausea, vomiting, diarrhea, enteritis, and stomatitis. Other GI toxicity that occurred in patients who received floxuridine were duodenal ulcer (peptic ulcer), duodenitis, gastritis, GI bleeding, gastroenteritis, glossitis, pharyngitis, anorexia, cramps, and abdominal pain. Discontinue floxuridine therapy in patients who develop stomatitis or (esophago) pharyngitis, intractable vomiting, diarrhea or frequent bowel movements/watery stools, or GI ulceration and bleeding.
Anemia, leukopenia, and thrombocytopenia have been reported commonly in patients who received arterial infusions of floxuridine. Intra-arterial floxuridine is rapidly catabolized to 5-fluorouracil and may have the same toxic and antimetabolic effects as 5-fluorouracil including pancytopenia and agranulocytosis. Monitor white blood cell (WBC) and platelet counts. Discontinue floxuridine therapy in patients who develop leukopenia (WBC < 3500/mm3), a rapidly falling WBC count, a platelet count less than 100,000/mm3, or bleeding from any site.
Localized erythema has been reported with an arterial infusion of floxuridine. Other dermatologic toxicities that occurred in patients who received floxuridine were alopecia, dermatitis, nonspecific skin toxicity, and rash (unspecified). Intra-arterial floxuridine is rapidly catabolized to 5-fluorouracil and may have the same toxic and antimetabolic effects as 5-fluorouracil including xerosis, fissuring, photosensitivity, maculopapular rash with pruritus, skin hyperpigmentation, vein pigmentation, and nail changes and nail loss.
Intra-arterial floxuridine is rapidly catabolized to 5-fluorouracil and may have the same toxic and antimetabolic effects as 5-fluorouracil including acute cerebellar syndrome, nystagmus, headache, disorientation, confusion, and euphoria.
Myocardial ischemia occurred in patients who received arterial infusions of floxuridine. Intra-arterial floxuridine is rapidly catabolized to 5-fluorouracil and may have the same toxic and antimetabolic effects as 5-fluorouracil including angina. Discontinue floxuridine therapy in patients who develop myocardial ischemia.
Intra-arterial floxuridine is rapidly catabolized to 5-fluorouracil and may have the same toxic and antimetabolic effects as 5-fluorouracil including anaphylactoid reactions (e.g., anaphylaxis).
Intra-arterial floxuridine is rapidly catabolized to 5-fluorouracil and may have the same toxic and antimetabolic effects as 5-fluorouracil including lacrimal duct stenosis, visual impairment, lacrimation, and photophobia.
Lethargy, malaise, and weakness have been reported in patients who received arterial infusions of floxuridine.
Fever and infection including abscess and catheter-related infections have been reported in patients who received arterial infusions of floxuridine.
Injection site reaction including bleeding at catheter site and catheter blocked, displaced or leaking have been reported in patients who received arterial infusions of floxuridine.
Arterial aneurysm and arterial ischemia have been reported in patients who received arterial infusions of floxuridine. Other procedural complications of regional arterial infusion that occurred with floxuridine use includes arterial thrombosis, thromboembolism, fibromyositis, and (thrombo) phlebitis.
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.
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 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.
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.
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.
Patients with renal impairment may have decreased floxuridine elimination. Drug accumulation and potential toxicity may occur. Dosage adjustments may be necessary.
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.
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.
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 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.
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.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available.
*non-FDA-approved indication
Acetaminophen; 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.
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.
Amlodipine; 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.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) 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.
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.
Bupivacaine; 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.
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.
Celecoxib; Tramadol: (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.
Chikungunya Vaccine, Live: (Contraindicated) 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.
Chlorpheniramine; 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.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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.
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.
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.
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.
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; Famotidine: (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.
Intranasal Influenza Vaccine: (Contraindicated) 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.
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.
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: (Contraindicated) 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.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) 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.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) 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; Esomeprazole: (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.
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.
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.
Pretomanid: (Major) Avoid coadministration of pretomanid with floxuridine, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications.
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.
Rotavirus Vaccine: (Contraindicated) 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.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) 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.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) 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.
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.
Sumatriptan; 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.
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.
Typhoid Vaccine: (Contraindicated) 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.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) 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.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with floxuridine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Floxuridine is a CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Yellow Fever Vaccine, Live: (Contraindicated) 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.
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.
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.
-Special Populations
Hepatic Impairment
Compromised hepatic function does not necessitate a dosage adjustment for floxuridine.
Renal Impairment
Compromised renal function does not necessitate a dosage adjustment for floxuridine.