Floxuridine (Systemic)


VA CLASSIFICATION
Primary: AN300

Commonly used brand name(s): FUDR.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antineoplastic. —

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Carcinoma, colorectal (treatment)
Carcinoma, hepatic (treatment)
[Carcinoma, ovarian, epithelial (treatment)]or
[Carcinoma, renal (treatment)]—Floxuridine, given by continuous regional intra-arterial infusion, is indicated for palliative management of colorectal carcinoma metastatic to the liver that has not responded to other treatment {01}. Floxuridine is most useful when the disease has not extended beyond an area capable of infusion via a single artery.
—Floxuridine also is indicated for carcinoma of the ovary and kidney not responsive to other antimetabolites.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    246.20 {04}

Mechanism of action/Effect:

Floxuridine is an antimetabolite of the pyrimidine analog type. Floxuridine is considered to be cell cycle–specific for the S-phase of cell division. Activity occurs as the result of activation in the tissues, and includes inhibition of DNA and, as a result of action of the fluorouracil metabolite, RNA synthesis.

Distribution:

Some crosses the blood-brain barrier; active metabolites are localized intracellularly.

Biotransformation:

Hepatic and in tissues, extensive, to the monophosphate derivative and fluorouracil; after continuous intra-arterial infusion, conversion to the monophosphate derivative is enhanced; largely converted to fluorouracil after rapid intravenous or intra-arterial injection.

Elimination:
    Respiratory (as carbon dioxide), about 60%.
    Renal, 10 to 13% (as unchanged drug and metabolites).


Precautions to Consider

Carcinogenicity

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents.

Studies with floxuridine have not been done {01}.

Antimetabolites have been shown to be carcinogenic in animals and may be associated with an increased risk of development of secondary carcinomas in humans, although the risk appears to be less than with alkylating agents.

Mutagenicity

Floxuridine produces oncogenic transformation of fibroblasts {01} in cultured C3H/10T1/2 mouse embryo cells.

Floxuridine is mutagenic in human leukocytes in vitro and in the Drosophila test system {01}.

Pregnancy/Reproduction
Fertility—
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents.

Studies with floxuridine have not been done. However, fluorouracil, which is a metabolite of floxuridine, has significant effects on fertility in animals {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.

First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered.

Other hazards to the fetus include adverse reactions seen in adults.

In general, use of a contraceptive is recommended during cytotoxic drug therapy.

Floxuridine is teratogenic in chick embryos, mice (at doses of 2.5 to 100 mg per kg of body weight [mg/kg]), and rats (at doses of 75 to 150 mg/kg) {01}; doses were 3.2 to 125 times, respectively, the recommended human therapeutic dose {01}. Malformations included cleft palates, skeletal defects, and deformed appendages, paws, and tails {01}.

FDA Pregnancy Category D {01}.

Breast-feeding

It is not known whether floxuridine is distributed into breast milk {01}. Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended during chemotherapy, because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity).

Pediatrics

No information is available on the relationship of age to the effects of floxuridine in pediatric patients.


Geriatrics


Although appropriate studies on the relationship of age to the effects of floxuridine have not been performed in the geriatric population, geriatrics-specific problems are not expected to limit the usefulness of this medication in the elderly. However, elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage in patients receiving floxuridine.


Dental

The bone marrow depressant effects of floxuridine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Floxuridine also commonly causes stomatitis, which may be associated with considerable discomfort.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of floxuridine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of floxuridine, if necessary, should be based on blood counts)


» Bone marrow depressants, other (see Appendix II) or
Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by floxuridine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by floxuridine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the floxuridine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Immunization with oral poliovirus vaccine should also be postponed in persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT]) and
Lactate dehydrogenase (LDH)     (serum values may be increased; possible chemical hepatitis or biliary sclerosis {03})


Bilirubin, serum     (concentrations may be increased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


» Hepatic function impairment    (reduced biotransformation; lower dosage is recommended)


» Hepatitis, history of    (increased risk of chemical hepatitis)


» Infection
» Renal function impairment    (reduced elimination; lower dosage is recommended)


Sensitivity to floxuridine
» Extreme caution should be used also in patients who have had previous cytotoxic drug therapy with alkylating agents or high-dose pelvic radiation therapy; a lower dosage is recommended.

Patient monitoring
The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; (» = major clinical significance):
Alanine aminotransferase (ALT [SGPT]) values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin concentrations, serum and
Lactate dehydrogenase (LDH) values, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


» Examination of patient's mouth for ulceration    (recommended before administration of each dose)


» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
» Platelet count    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)




Side/Adverse Effects

Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.
Floxuridine is a highly toxic medication and serious toxic effects frequently occur. When floxuridine is administered intra-arterially, local reactions are more prominent than systemic reactions.
Because floxuridine is converted to fluorouracil, there is a possibility that some side/adverse effects associated with fluorouracil may also occur {01}.
Adverse effects associated with prolonged use of an arterial catheter include arterial ischemia, thrombosis, bleeding at the catheter site, blocked catheters, leakage at the site, embolism, fibromyositis, infection at the catheter site, abscesses, thrombophlebitis, and perforation of the duodenum or stomach.
Floxuridine administered via hepatic artery infusion may cause a chemical hepatitis, characterized by elevated hepatic enzymes and nausea and vomiting. However, elevated hepatic enzymes may also be a sign of biliary sclerosis {03}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Aphthous stomatitis (sores in mouth and on lips)
    
enteritis (diarrhea; stomach pain or cramps)

Incidence less frequent
    
Displaced hepatic artery catheter (heartburn; black tarry stools)
    
esophagopharyngitis{02} (heartburn)
    
gastrointestinal ulceration or gastritis (black tarry stools)
    
glossitis (swelling or soreness of tongue)
    
nausea and vomiting
    
scaling or redness of hands or feet —with prolonged infusion therapy

Incidence rare
    
Anemia (unusual tiredness or weakness)
    
hepatotoxicity or intra- and extrahepatic biliary sclerosis{01}{03} or acalculus cholecystitis{01} (yellow eyes or skin)
    
leukopenia or infection (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—usually asymptomatic
    
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic
    
trouble in walking



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent or rare
    
Loss of appetite
    
skin rash or itching



Those not indicating need for medical attention
Incidence less frequent or rare
    
Thinning of hair





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Floxuridine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to floxuridine

Pregnancy—Use not recommended because of mutagenic, teratogenic, and carcinogenic potential; advisability of using contraception; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of risk of serious side effects
Other medications, especially other bone marrow depressants or previous cytotoxic drug or radiation therapy
Other medical problems, especially chickenpox, herpes zoster, hepatic function impairment, history of hepatitis, infection, or renal function impairment

Proper use of this medication
» Telling physician about nausea and vomiting, especially with stomach pain

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by physician

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth


Side/adverse effects
May cause adverse effects such as blood problems, inflammation of gastrointestinal tract, chemical hepatitis, and cancer; importance of discussing possible effects with physician

Signs of potential side effects, especially aphthous stomatitis, enteritis, displaced hepatic artery catheter, esophagopharyngitis, gastrointestinal ulceration, gastritis, glossitis, nausea and vomiting, scaling or redness of hands or feet, anemia, hepatotoxicity, intra- and extrahepatic biliary sclerosis, acalculus cholecystitis, leukopenia, infection, thrombocytopenia, and trouble in walking

Physician or nurse can help in dealing with side effects

Possibility of thinning of hair; normal hair growth should return after treatment has ended


General Dosing Information
Patients receiving floxuridine should be under supervision of a physician experienced in antimetabolite chemotherapy and the technique of intra-arterial infusion.

Floxuridine is recommended mainly for intra-arterial use. Use of an appropriate infusion pump is recommended to ensure a uniform rate of infusion. In selected patients, a portable or implantable pump may be used.

Therapy with floxuridine is continued as long as a response occurs, which may vary from 1 week to several months (with appropriate rest periods). However, floxuridine is an extremely toxic medication; therapy should be discontinued promptly at the first sign of:

• Diarrhea (five or more loose stools daily) {01}


• Esophagopharyngitis {01}


• Gastrointestinal ulceration and bleeding {01}


• Hemorrhage from any site {01}


• Leukopenia (particularly granulocytopenia), marked {01}


• Myocardial ischemia {01}


• Stomatitis {01}


• Thrombocytopenia, marked {01}


• Vomiting, intractable {01}
Therapy may be reinitiated at a lower dosage when side effects have subsided.

Floxuridine should be withdrawn if signs of obstructive jaundice occur and reinstituted only after careful evaluation of the patient. {03}

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of floxuridine. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.

Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include:    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.


Parenteral Dosage Forms

FLOXURIDINE STERILE USP

Usual adult dose
Carcinoma, colorectal or
Carcinoma, hepatic
Intra-arterial, 100 to 600 mcg (0.1 to 0.6 mg) per kg of body weight per day continuously over twenty-four hours {01}, continued until toxicity or a response occurs, usually for fourteen to twenty-one days, with a rest period of two weeks between courses.


Usual pediatric dose
Safety and efficacy have not been established {01}.

Size(s) usually available:
U.S.—


500 mg (Rx) [FUDR][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light.

Preparation of dosage form:
Sterile Floxuridine USP is reconstituted for use by adding 5 mL of sterile water for injection to the vial; may be further diluted in 5% dextrose injection or 0.9% sodium chloride injection for administration by infusion.

Stability:
Reconstituted solutions of floxuridine are stable at 2 to 8 °C (36 to 46 °F) for not more than 2 weeks.



Revised: 09/30/1997



References

Note: References used in the development and subsequent revision of this monograph have not been incorporated into the database and therefore are not listed below.

  1. FUDR package insert (Roche—US), Rev 5/78; Rev 4/87; Rev 10/89.
  1. Panel comment, 1987.
  1. Bolton JS; Bowen JC. Biliary sclerosis associated with hepatic artery infusion of floxuridine. Surgery 1986 Jan; 99(1): 119-22.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1997. p. 313.
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