Floxuridine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Injection:

Generic: 0.5 g (1 ea)

Pharmacology

Mechanism of Action

Floxuridine is catabolized to fluorouracil after intra-arterial administration, resulting in activity similar to fluorouracil; inhibits thymidylate synthetase and disrupts DNA and RNA synthesis.

Pharmacokinetics/Pharmacodynamics

Metabolism

Hepatic; Active metabolites: Floxuridine monophosphate (FUDR-MP) and fluorouracil; Inactive metabolites: Urea, CO₂, α-fluoro-β-alanine, α-fluoro-β-guanidopropionic acid, α-fluoro-β-ureidopropionic acid, and dihydrofluorouracil

Excretion

Urine: As fluorouracil, urea, α-fluoro-β-alanine, α-fluoro-β-guanidopropionic acid, α-fluoro-β-ureidopropionic acid, and dihydrofluorouracil; Respiratory (as exhaled gases [CO₂])

Use: Labeled Indications

Colorectal cancer, hepatic metastases: Palliative management of hepatic metastases of colorectal cancer (administered by continuous regional hepatic intra-arterial infusion) in select patients considered incurable by surgical resection or other means.

Limitation of use: Patients with known disease extending beyond an area capable of a single artery infusion should (in most cases) be considered for systemic chemotherapy with other agents.

Contraindications

Poor nutritional states; depressed bone marrow function; potentially serious infections

Dosage and Administration

Dosing: Adult

Colorectal cancer, hepatic metastases: Hepatic intra-arterial (off-label combination): 0.25 mg/kg/day (with dexamethasone and heparin) continuous infusion for 14 days during a 5-week cycle for 6 cycles (in combination with 6 cycles of fluorouracil and leucovorin; begin floxuridine 2 weeks after the fluorouracil and leucovorin cycle) (Kemeny 1999).

Manufacturer’s labeling: Dosing in the prescribing information may not reflect current clinical practice. Range: 0.1 to 0.6 mg/kg/day as a continuous infusion; Usual dose: 0.4 to 0.6 mg/kg/day as a continuous infusion; continue until intolerable toxicity.

Dosing: Adjustment for Toxicity

Withhold therapy for adverse reactions; may resume if adverse reaction subsides.

Hematologic: Discontinue for white blood count <3,500/mm³ (or is falling rapidly) or for platelet count <100,000/mm³.

Nonhematologic toxicity: Discontinue for myocardial ischemia, stomatitis/esophagopharyngitis, vomiting (intractable), diarrhea (or frequent/watery stools), gastrointestinal ulceration/bleeding, hemorrhage (from any site).

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Reconstitute each 500 mg vial with 5 mL SWFI to a final concentration of 100 mg/mL. Further dilute in D5W or NS to a volume appropriate for intra-arterial administration. Floxuridine has been reported to be mixed with dexamethasone and heparin to a total volume of 50 mL in NS (Kemeny 1999).

Administration

Administer as a continuous hepatic intra-arterial infusion using an infusion pump.

Storage

Store intact vials at 20°C to 25°C (68°F to 77°F). Reconstituted vials are stable for up to 2 weeks under refrigeration at 2°C to 8°C (36°F to 46°F). Follow USP 797 recommendations for beyond use dates based on the level of risk for preparation.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cimetidine: May increase the serum concentration of Fluorouracil Products. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Folic Acid: May enhance the adverse/toxic effect of Fluorouracil Products. Monitor therapy

Fosphenytoin-Phenytoin: Fluorouracil Products may increase the serum concentration of Fosphenytoin-Phenytoin. Monitor therapy

Gimeracil: May increase the serum concentration of Fluorouracil Products. Avoid combination

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Leucovorin Calcium-Levoleucovorin: May enhance the adverse/toxic effect of Fluorouracil Products. Monitor therapy

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

MetroNIDAZOLE (Systemic): May increase the serum concentration of Fluorouracil Products. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Vitamin K Antagonists (eg, warfarin): Fluorouracil Products may increase the serum concentration of Vitamin K Antagonists. Management: Monitor INR and for signs/symptoms of bleeding closely when a fluorouracil product is combined with a vitamin K antagonist (eg, warfarin). Anticoagulant dose adjustment will likely be necessary. Consider therapy modification

Adverse Reactions

>10%:

Gastrointestinal: Diarrhea (may be dose limiting), stomatitis

Hematologic & oncologic: Anemia, bone marrow depression (nadir: 7-10 days; may be dose limiting), leukopenia, thrombocytopenia

1% to 10%:

Dermatologic: Alopecia, dermatitis, localized erythema, skin hyperpigmentation, skin photosensitivity

Gastrointestinal: Anorexia, biliary sclerosis, cholecystitis

Hepatic: Jaundice

<1%, postmarketing, and/or case reports: Abdominal cramps, abdominal pain, BSP abnormality, change in prothrombin time, decreased erythrocyte sedimentation rate, decreased serum total protein, duodenal ulcer, duodenitis, enteritis, fever, gastritis, gastroenteritis, gastrointestinal hemorrhage, gastrointestinal ulcer, glossitis, hemorrhage, hepatic abscess, increased erythrocyte sedimentation rate, increased lactate dehydrogenase, increased serum alkaline phosphatase, increased serum bilirubin, increased serum total protein, increased serum transaminases, infusion related reaction (arterial aneurysm; arterial ischemia; arterial thrombosis; embolism; fibromyositis; thrombophlebitis; hepatic necrosis; abscesses; infection at catheter site; bleeding at catheter site; catheter blocked, displaced, or leaking), ischemic heart disease, lethargy, malaise, nausea, pharyngitis, skin rash, vomiting, weakness

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Floxuridine may cause severe hematologic toxicity; anemia, leukopenia, and thrombocytopenia commonly occur. The nadir is usually at 7 to 10 days (Perry 2012). Leukopenia or thrombocytopenia may require therapy discontinuation.
• Cardiovascular toxicity: Myocardial ischemia has been reported; discontinue promptly if occurs.
• Gastrointestinal toxicity: May cause gastrointestinal toxicity. Discontinue at the first sign of stomatitis or esophagopharyngitis; discontinue for intractable vomiting, diarrhea, or gastrointestinal ulceration/bleeding.
• Hemorrhage: Bleeding may occur; discontinue if hemorrhage (from any site) occurs.
• Toxicity: Toxicities may occur; monitor closely. Severe toxicities are more likely to occur in high risk patients, patients with prior pelvic irradiation, or in those who have received prior alkylating agents.

Disease-related concerns:

• Hepatic impairment: Use with extreme caution in patients with hepatic impairment.
• Renal impairment: Use with extreme caution in patients with renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of a physician experienced in cancer chemotherapy and in intra-arterial treatment.
• Appropriate use: [US Boxed Warning]: Due to the risk for severe toxic reactions, the manufacturer recommends that patients be hospitalized for initiation of the first treatment course. Not intended for use as an adjuvant to surgery.

Monitoring Parameters

Monitor CBC with differential and platelet count; liver function (bilirubin, alkaline phosphatase, and transaminases); monitor for signs/symptoms of stomatitis/esophagopharyngitis, gastrointestinal ulceration/bleeding, hemorrhage, vomiting, and/or diarrhea

Pregnancy

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse effects have been observed in animal reproduction studies. Floxuridine may cause fetal harm if administered during pregnancy. Medications that inhibit DNA synthesis are known to be teratogenic in humans. Females of reproductive potential should avoid pregnancy during floxuridine treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience hair loss, sore throat, abdominal cramps, or lack of appetite. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), chest pain, mouth irritation, mouth sores, diarrhea, severe nausea, vomiting, severe abdominal pain, dark urine, yellow skin, or severe loss of strength and energy (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.