VA Class:AN300
Floxuridine, a pyrimidine antagonist, is an antimetabolite antineoplastic agent.
Floxuridine is administered by continuous regional intra-arterial infusion in the palliative management of adenocarcinoma of the GI tract that has metastasized to the liver in selected patients who are considered to be incurable by surgery or other means of cancer therapy.102, 105 Floxuridine is not intended to be used as an adjuvant to surgery.105 Patients with carcinoma extending beyond an area capable of being infused via a single artery should usually be considered for therapy with other systemic chemotherapeutic agents.105 The optimal efficacy and sequence of combination therapy of floxuridine with other antineoplastic agents or with irradiation require further investigation10, 35, 36 and it should be kept in mind that any form of therapy that adds to the stress of the patient, interferes with nutrition, or depresses bone marrow function will increase floxuridine toxicity.105
Intra-arterial floxuridine also is used for the palliative treatment of primary† and secondary carcinomas of the liver.102
Reconstitution and Administration
Floxuridine is administered by continuous intra-arterial infusion via a catheter inserted into the arterial blood supply of the tumor. Floxuridine sterile powder is reconstituted by adding 5 mL of sterile water for injection to the vial labeled as containing 500 mg of the drug in order to provide a solution containing 100 mg/mL.105 The calculated daily dose of the drug is usually diluted with 5% dextrose or 0.9% sodium chloride injection to a volume appropriate for the infusion apparatus used.105 An infusion pump may be used to overcome pressure in large arteries and to ensure a uniform rate of infusion.105
Floxuridine solutions should be inspected visually for particulate matter and discoloration whenever solution and container permit.105
Dosage of floxuridine must be based on the clinical and hematologic response and tolerance of the patient in order to obtain optimum therapeutic results with minimum adverse effects. Clinicians should consult published protocols for the dosage of floxuridine and other chemotherapeutic agents and the method and sequence of administration.
The usual dosage of floxuridine by continuous intra-arterial infusion is 0.1-0.6 mg/kg daily.105 The higher dosages (0.4-0.6 mg/kg daily) are usually used for hepatic artery infusion since the liver metabolizes the drug and thus reduces the risk of systemic toxicity.105 Floxuridine therapy may be continued until toxicity occurs.105 In patients undergoing hepatic artery infusion, local toxicity may be manifested by increasingly abnormal liver function tests, anorexia, and abdominal cramps. An adequate course of therapy generally requires 1-6 weeks of continuous administration of the drug. Sterile water for injection has been infused between courses of floxuridine therapy to keep the catheter open. When signs of floxuridine toxicity have subsided, therapy may be resumed.105 The patient should be maintained on floxuridine therapy as long as response to the drug continues.105
Toxic effects following intra-arterial infusion of floxuridine are generally related to the drug-infused area.105 Systemic toxicity has been reported to occur in patients receiving recommended doses of floxuridine by intra-arterial infusion and the possibility of systemic reactions should be considered. The major systemic toxic effects of floxuridine are on the normal, rapidly proliferating tissues, particularly of the bone marrow and lining of the GI tract.
Floxuridine is metabolized to fluorouracil, but the full spectrum of fluorouracil toxicity is not expected with floxuridine because of regional administration of the drug by intra-arterial infusion.105 However, the possibility of typical adverse effects of fluorouracil during floxuridine therapy should be considered.105
Nausea, vomiting, and diarrhea are common adverse effects; anorexia, cramps, and pain also may occur.105 Stomatitis is one of the most common signs of specific toxicity.105 Enteritis occurs frequently and duodenal ulcer, duodenitis, gastritis, gastroenteritis, glossitis, GI bleeding, and pharyngitis also have been reported.105
Leukopenia and anemia occur commonly with floxuridine therapy; thrombocytopenia also may occur.105 The patient's hematologic status must be carefully monitored.105 (See Cautions: Precautions and Contraindications.)
Pancytopenia and agranulocytosis have been reported in patients receiving fluorouracil; because of its pharmacologic similarity, these adverse hematologic effects might occur in patients receiving floxuridine.105
Dermatologic and Sensitivity Reactions
The most common type of dermatologic toxicity is localized erythema.105 Other dermatologic manifestations of floxuridine toxicity have included alopecia, dermatitis, nonspecific skin toxicity, and rash.105 Edema, excoriation, maceration, pruritus, and ulceration also have been reported in patients receiving floxuridine.106
Dry skin, fissuring, pruritic maculopapular rash, increased pigmentation of the skin, vein pigmentation, and nail changes, including loss of nails, have been reported in patients receiving fluorouracil; because of its pharmacologic similarity, these adverse dermatologic effects might occur in patients receiving floxuridine.105
Anaphylaxis and generalized allergic reactions as well as photosensitivity have been reported in patients receiving fluorouracil; because of its pharmacologic similarity, these sensitivity reactions might occur in patients receiving floxuridine.105
Elevations in serum alkaline phosphatase, aminotransferase, bilirubin, and lactic dehydrogenase concentrations occur frequently.105
Hepatic arterial infusions of floxuridine have been associated with sclerosis of the intrahepatic and/or extrahepatic bile ducts100, 101, 103, 104, 105 and cirrhosis of the liver.101, 103 Acalculus cholecystitis has been reported in patients receiving the drug.105
Myocardial ischemia has been reported in patients receiving floxuridine.105
Angina has been reported in patients receiving fluorouracil; because of its pharmacologic similarity, this adverse cardiovascular effect might occur in patients receiving floxuridine.105
Reported complications from intra-arterial infusion techniques include arterial aneurysm; arterial ischemia; arterial thrombosis; bleeding at the catheter site; blocked, displaced or leaking catheter; embolism; fibromyositis; infection at the catheter site; hepatic necrosis; abscesses; and thrombophlebitis.105 Inaccurate catheter placement and contamination of the infusion assembly also have been reported in patients receiving floxuridine.10
Hemiplegia, ataxia, seizures, nystagmus, blurred vision, vertigo, mental depression, and pain have been reported in patients receiving floxuridine.106
Acute cerebellar syndrome, headache, disorientation, confusion, and euphoria have been reported in patients receiving fluorouracil; because of its pharmacologic similarity, these adverse nervous system effects might occur in patients receiving floxuridine.105
Photophobia, visual changes, lacrimal duct stenosis, and lacrimation have been reported in patients receiving fluorouracil; because of its pharmacologic similarity, these adverse ocular effects might occur in patients receiving floxuridine.105
Abnormalities in sulfobromophthalein, prothrombin, total proteins, and sedimentation rate have been reported in patients receiving floxuridine.105 Other adverse effects occurring in patients receiving floxuridine include fever, lethargy, malaise, and weakness.105 Dysuria, hiccups, and hypoadrenalism also have been reported.106
Epistaxis has been reported in patients receiving fluorouracil; because of its pharmacologic similarity, this adverse effect might occur in patients receiving floxuridine.105
Precautions and Contraindications
Floxuridine is a highly toxic drug with a very low therapeutic index; a therapeutic response is not likely to occur without some evidence of toxicity.105 The drug can produce severe hematologic toxicity, GI hemorrhage, and even death despite careful selection of patients and adjustment of dosage.105 Floxuridine should be given only by, or under the supervision of, a clinician who is experienced in cancer chemotherapy and in intra-arterial drug therapy.105 Patients should be hospitalized at least during the initial course of therapy and should be informed of the expected toxic effects.105
If intractable vomiting or diarrhea occurs, floxuridine should be discontinued immediately.105 Appearance of stomatitis as evidenced by oral mucosal erythema or ulceration at the inner margin of the lips, or of esophagopharyngitis as evidenced by a sore throat or dysphagia, necessitates cessation of therapy.105 GI ulceration and bleeding, or hemorrhage at any site, requires prompt cessation of treatment.105
Leukocyte and platelet counts should be carefully monitored and if the leukocyte count falls to below 3500/mm3 or decreases rapidly, or if there is a fall in the platelet count to below 100,000/mm3, the drug should be discontinued.105 If myocardial ischemia occurs, floxuridine should be discontinued immediately.105
Floxuridine should be used with extreme caution in patients who have previously received high-dose pelvic irradiation therapy or alkylating agents and in patients with impaired liver or kidney function.105 Floxuridine is contraindicated in patients who are in a poor nutritional state, have depressed bone marrow function (generally a leukocyte count of 5000/mm3 or less and/or a platelet count of 100,000/mm3 or less), or have potentially serious infections because these patients are more likely to develop serious toxicity than are patients in relatively good condition.105 Although severe toxicity is more likely in poor-risk patients, fatalities occasionally may occur even in patients in relatively good condition.105
Patients receiving floxuridine therapy should be informed of the expected adverse effects, particularly oral manifestations.105 Patients also should be informed that floxuridine-induced alopecia, usually transient, may occur.105
Safety and efficacy of floxuridine in children have not been established.105
Mutagenicity and Carcinogenicity
Floxuridine has been shown to be mutagenic in human leukocytes in vitro and in the Drosophila test system.105 In addition, floxuridine has been shown to induce oncogenic transformation of fibroblasts from mouse embryo in vitro; however, the relationship between oncogenicity and mutagenicity is not fully understood.105 Fluorouracil, to which floxuridine is metabolized following intra-arterial administration, has been shown to be mutagenic in vitro.105
Long-term studies in animals to evaluate the carcinogenic potential of floxuridine have not been performed to date.105 The carcinogenic risk in humans is not known.105
Pregnancy, Fertility, and Lactation
Floxuridine may cause fetal harm when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus.105 Teratogenic effects have occurred in animals receiving floxuridine.105 Floxuridine has been shown to be teratogenic in the chick embryo, mouse (at doses of 2.5-100 mg/kg), and rat (at doses of 75-150 mg/kg); malformations observed in offspring included cleft palates, skeletal defects, and deformed appendages, paws, and tails.105 Floxuridine dosages resulting in teratogenic effects in animal studies were 4.2-125 times the recommended human therapeutic dose.105 There are no adequate and well-controlled studies using floxuridine in pregnant women.105 However, because floxuridine inhibits DNA synthesis, and other drugs that inhibit DNA synthesis have been reported to be teratogenic in humans, the possible teratogenic effects of floxuridine must be considered.105 Animal studies have not been conducted to date to evaluate the effects of floxuridine on perinatal or postnatal development; however, compounds such as floxuridine that inhibit synthesis of DNA, RNA, and protein may be expected to have adverse effects on fetal and child development.105
Floxuridine should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.105 When the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.105 Women of childbearing potential should be advised to avoid becoming pregnant while receiving the drug.105
Animal studies have not been conducted to date to evaluate the effects of floxuridine on fertility in males or females.105 However, fluorouracil, to which floxuridine is metabolized following intra-arterial administration, has been shown to induce chromosomal aberrations and changes in chromosome organization of spermatogonia in rats at intraperitoneal doses of 125 or 250 mg/kg.105 Fluorouracil also caused inhibition of spermatogonial differentiation, resulting in transient infertilty.105 Intraperitoneal administration of fluorouracil 25-50 mg/kg in female rats during the preovulatory phase of oogenesis reduced the incidence of fertile matings, delayed the development of preimplantation and postimplantation embryos, increased the incidence of preimplantation lethality, and induced chromosomal anomalies in the embryos.105 Because floxuridine interferes with the synthesis of DNA, RNA, and protein, the drug may be expected to have adverse effects on gametogenesis.105
It is not known whether floxuridine is distributed into milk.105 Floxuridine inhibits the synthesis of DNA and RNA.105 Because of the potential for serious adverse reactions to floxuridine in nursing infants, nursing should not be undertaken by women receiving the drug.105
Limited information is available on the acute toxicity of floxuridine.105 The manufacturer states that because of the regional method of administration via intra-arterial injection, overdosage of floxuridine is unlikely to occur.105 The acute lethal dose of floxuridine (in mg/kg ± standard error) is 157±46 in dogs, 94±20 in rabbits, 670±73 in rats, and 880±51 in mice.105
The expected manifestations of floxuridine overdosage include nausea, vomiting, diarrhea, GI ulceration and bleeding, and bone marrow depression (i.e., thrombocytopenia, leukopenia, and agranulocytosis).105
There is no known specific antidote for floxuridine overdosage.105 Patients who receive an overdosage of floxuridine should be monitored hematologically for at least 4 weeks.105 In the event of observed toxicity, appropriate supportive therapy should be initiated.105
Floxuridine is an antimetabolite. The monophosphate of the drug, 5-fluoro-2'-deoxyuridine-5'-phosphate (FUDR-MP), inhibits thymidylate synthetase, thus inhibiting methylation of deoxyuridylic acid to thymidylic acid and thereby interfering with the synthesis of DNA. Following administration of a single dose of floxuridine, the drug is catabolized to fluorouracil and produces the same antimetabolic effects as the latter drug.105 In addition to interfering with DNA synthesis, metabolites of fluorouracil become incorporated to a small extent into RNA, producing a fraudulent RNA. Fluorouracil also inhibits utilization of preformed uracil in RNA synthesis by blocking uracil riboside phosphorylase.
Following infusion of small doses of floxuridine, most of the drug appears to be anabolized to FUDR-MP, the active metabolite of the drug. When single doses are administered rapidly, floxuridine is apparently rapidly catabolized to fluorouracil. It has been suggested that the fluorinated pyrimidines may have some specificity against certain tumors in comparison with normal tissues; however, such specificity has not been established. Floxuridine and fluorouracil are metabolized in the liver. Metabolic degradation of floxuridine is less when the drug is given by continuous infusion than when given by single injections. The drug is excreted intact and as urea, fluorouracil, α-fluoro-β-ureidopropionic acid, dihydrofluorouracil, α-fluoro-β-guanidopropionic acid, and α-fluoro-β-alanine in the urine and as respiratory carbon dioxide.
Floxuridine is a pyrimidine antagonist. The drug is a nucleoside consisting of the pyrimidine base fluorouracil, and the sugar deoxyribose. Floxuridine occurs as a white to practically white powder and is freely soluble in water105 and soluble in alcohol. Following reconstitution with sterile water for injection, floxuridine injection has a pH of 4-5.5.105
Floxuridine sterile powder should be protected from light and stored at 15-30°C. In the dry state, floxuridine has an expiration date of 3 years following the date of manufacture. Reconstituted floxuridine injection should be stored at 2-8°C and used within 2 weeks.105
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for intra-arterial infusion only | 500 mg* | Floxuridine for Injection | |
FUDR® |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
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