FUDR

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FUDR

Classes

Pyrimidine Analogs

Administration

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.

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.

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

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.

Common Brand Names

FUDR

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.

Dosage And 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

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.

Drug Interactions

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.
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.
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.
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.
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.
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: (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.
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.
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.
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) 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.

How Supplied

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

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.

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.

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.