Floxuridine for Injection USP, an antineoplastic antimetabolite, is available as a sterile, nonpyrogenic, lyophilized powder for reconstitution. Each vial contains 500 mg of floxuridine which is to be reconstituted with 5 mL of sterile water for injection. An appropriate amount of reconstituted solution is then diluted with a parenteral solution for intra-arterial infusion (see DOSAGE AND ADMINISTRATION section).

Floxuridine is a fluorinated pyrimidine. Chemically, floxuridine is 2'-Deoxy-5-fluorouridine, with a molecular formula of C₉H₁₁FN₂O₅. It is a white to off-white odorless solid which is freely soluble in water.

The 2% aqueous solution has a pH of between 4.0 and 5.5. The molecular weight of floxuridine is 246.20 and the structural formula is:

Floxuridine is effective in the palliative management of gastrointestinal adenocarcinoma metastatic to the liver, when given by continuous regional intra-arterial infusion in carefully selected patients who are considered incurable by surgery or other means. Patients with known disease extending beyond an area capable of infusion via a single artery should, except in unusual circumstances, be considered for systemic therapy with other chemotherapeutic agents.

Each vial must be reconstituted with 5 mL of sterile water for injection to yield a solution containing approximately 100 mg of floxuridine/mL. The calculated daily dose(s) of the drug is then diluted with 5% dextrose or 0.9% sodium chloride injection to a volume appropriate for the infusion apparatus to be used. The administration of floxuridine is best achieved with the use of an appropriate pump to overcome pressure in large arteries and to ensure a uniform rate of infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

The recommended therapeutic dosage schedule of floxuridine by continuous arterial infusion is 0.1 to 0.6 mg/kg/day. The higher dosage ranges (0.4 to 0.6 mg) are usually employed for hepatic artery infusion because the liver metabolizes the drug, thus reducing the potential for systemic toxicity.

Therapy can be given until adverse reactions appear. (See PRECAUTIONS section.) When these side effects have subsided, therapy may be resumed. The patient should be maintained on therapy as long as response to floxuridine continues.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.^1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Floxuridine for Injection USP, 500 mg, lyophilized, in a 5 mL vial, is supplied in individual cartons. NDC 55390-135-01. This is to be reconstituted with 5 mL sterile water for injection.The sterile powder should be stored at 15° to 30°C (59° to 86°F). Reconstituted vials should be stored under refrigeration 2° to 8°C (36° to 46°F) for not more than 2 weeks.

REFERENCE

1. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC, US Government Printing Office, NIH publication 83-2621.

2. AMA Council Report. Guidelines for handling parenteral antineoplastics. JAMA. Mar 15, 1985, 253:1590-1592.

3. National Study Commission on Cytotoxic Exposure:Recommendation for handling cytotoxic agents. Available from Louis P.Jeffrey, ScD, Director of Pharmacy Services, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02902.

4. Clinical Oncological Society of Australia: Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. Apr 30, 1983, 1:426-428.

5. Jones, RB, Frank R, Mass T: Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA. Sept - Oct, 1983, 33:258-263.

6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. AMJHosp Pharm 1990:47:1033-1049.

7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES). AMJHealth-Syst Pharm. 1996:53:1669-1685.

Manufactured by: Ben Venue Laboratories Inc. Bedford, OH 44146. Manufactured for: Bedford Laboratories™ Bedford, OH 44146. February 2000. FDA revision date: 7/1/2002

Adverse reactions to the arterial infusion of floxuridine are generally related to the procedural complications of regional arterial infusion.

The more common adverse reactions to the drug are nausea, vomiting, diarrhea, enteritis, stomatitis and localized erythema. The more common laboratory abnormalities are anemia, leukopenia, thrombo-cytopenia and elevations of alkaline phosphatase, serum transaminase, serum bilirubin and lactic dehydrogenase.

Other adverse reactions are:

Gastrointestinal: duodenal ulcer, duodenitis, gastritis, bleeding, gastroenteritis, glossitis, pharyngitis, anorexia, cramps, abdominal pain;possible intra- and extrahepatic biliary sclerosis, as well as acalculous cholecystitis.

Dermatologic: alopecia, dermatitis, nonspecific skin toxicity, rash.

Cardiovascular: myocardial ischemia.

Miscellaneous Clinical Reactions: fever, lethargy, malaise, weakness.

Laboratory Abnormalities: BSP, prothrombin, total proteins, sedimentation rate and thrombopenia.

Procedural Complications of Regional Arterial Infusion: 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.

The following adverse reactions have not been reported with floxuridine but have been noted following the administration of 5-fluorouracil. While the possibility of these occurring following floxuridine therapy is remote because of its regional administration, one should be alert for these reactions following the administration of floxuridine because of the pharmacological similarity of these two drugs: pancytopenia, agranulocytosis, myocardial ischemia, angina, anaphylaxis, generalized allergic reactions, acute cerebellar syndrome, nystagmus, headache, dry skin, fissuring, photosensitivity, pruritic maculopapular rash, increased pigmentation of the skin, vein pigmentation, lacrimal duct stenosis, visual changes, lacrimation, photophobia, disorientation, confusion, euphoria, epistaxis and nail changes, including loss of nails.

See WARNINGS section.

BECAUSE OF THE POSSIBILITY OF SEVERE TOXIC REACTIONS, ALL PATIENTS SHOULD BE HOSPITALIZED FOR THE FIRST COURSE OF THERAPY.

Floxuridine should be used with extreme caution in poor risk patients with impaired hepatic or renal function or a history of high-dose pelvic irradiation or previous use of alkylating agents. The drug is not intended as an adjuvant to surgery.

Floxuridine may cause fetal harm when administered to a pregnant woman. It has been shown to be teratogenic in the chick embryo, mouse (at doses of 2.5 to 100 mg/kg) and rat (at doses of 75 to 150 mg/kg). Malformations included cleft palates; skeletal defects; and deformed appendages, paws and tails. The dosages which were teratogenic in animals are 4.2 to 125 times the recommended human therapeutic dose.

There are no adequate and well-controlled studies with floxuridine in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Combination Therapy: Any form of therapy which adds to the stress of the patient, interferes with nutrition or depresses bone marrow function will increase the toxicity of floxuridine.

General

Floxuridine is a highly toxic drug with a narrow margin of safety. Therefore, patients should be carefully supervised since therapeutic response is unlikely to occur without some evidence of toxicity. Severe hematological toxicity, gastrointestinal hemorrhage and even death may result from the use of floxuridine despite meticulous selection of patients and careful adjustment of dosage. Although severe toxicity is more likely in poor risk patients, fatalities may be encountered occasionally even in patients in relatively good condition.

Therapy is to be discontinued promptly whenever one of the following signs of toxicity appears:

Myocardial ischemia
Stomatitis or esophagopharyngitis, at the first visible sign
Leukopenia (WBC under 3500) or a rapidly falling white blood count
Vomiting, intractable
Diarrhea, frequent bowel movements or watery stools
Gastrointestinal ulceration and bleeding
Thrombocytopenia (platelets under 100,000)
Hemorrhage from any site

Laboratory Tests

Careful monitoring of the white blood count and platelet count is recommended.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Long-term studies in animals to evaluate the carcinogenic potential of floxuridine have not been conducted. On the basis of the available data, no evaluation can be made of the carcinogenic risk of floxuridine to humans.

Mutagenesis: Oncogenic transformation of fibroblasts from mouse embryo has been induced in vitro by floxuridine, but the relationship between oncogenicity and mutagenicity is not clear. Floxuridine has also been shown to be mutagenic in human leukocytesin vitro and in the Drosophila test system. In addition, 5-fluorouracil, to which floxuridine is catabolized when given by intra-arterial injection, has been shown to be mutagenic in in vitro tests.

Impairment of Fertility: The effects of floxuridine on fertility and general reproductive performance have not been studied in animals. However, because floxuridine is catabolized to 5-fluorouracil, it should be noted the 5-fluorouracil has been shown to induce chromosomal aberrations and changes in chromosome organization of spermatogonia in rats at doses of 125 or 250 mg/kg, administered intraperitoneally.

Spermatogonial differentiation was also inhibited by fluorouracil, resulting in transient infertility. In female rats, fluorouracil, administered intraperitoneally at doses of 25 or 50 mg/kg during the preovulatory phase of oogenesis, significantly reduced the incidence of fertile matings, delayed the development of pre- and post-implantation embryos, increased the incidence of preimplantation lethality and induced chromosomal anomalies in these embryos. Compounds such as floxuridine, which interfere with DNA, RNA and protein synthesis, might be expected to have adverse effects on gametogenesis.

Pregnancy

Teratogenic Effects: Pregnancy Category D.

See WARNINGS section. Floxuridine has been shown to be teratogenic in the chick embryo, mouse (at doses of 2.5 to 100 mg/kg) and rat (at doses of 75 to 150 mg/kg). Malformations included cleft palates, skeletal defects and deformed appendages, paws and tails. The dosages which were teratogenic in animals were 4.2 to 125 times the recommended human therapeutic dose.

There are no adequate and well-controlled studies with floxuridine in pregnant women. While there is no evidence of teratogenicity in humans due to floxuridine, it should be kept in mind that other drugs which inhibit DNA synthesis (e.g., methotrexate and aminopterin) have been reported to be teratogenic in humans. Floxuridine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Floxuridine has not been studied in animals for its effects on peri- and postnatal development. However, compounds which inhibit DNA, RNA and protein synthesis might be expected to have adverse effects on peri- and postnatal development.

Nursing Mothers

It is not known whether floxuridine is excreted in human milk. Because floxuridine inhibits DNA and RNA synthesis, mothers should not nurse while receiving this drug.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

The possibility of overdosage with floxuridine is unlikely in view of the mode of administration. Nevertheless, the anticipated manifestations would be nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, bone marrow depression (including thrombocytopenia, leukopenia and agranulocytosis). No specific antidotal therapy exists. Patients who have been exposed to an overdosage of floxuridine should be monitored hematologically for at least 4 weeks. Should abnormalities appear, appropriate therapy should be utilized.

The acute intravenous toxicity of floxuridine is as follows:

Floxuridine therapy is contraindicated for patients in a poor nutritional state, those with depressed bone marrow function or those with potentially serious infections.

When floxuridine is given by rapid intra-arterial injection it is apparently rapidly catabolized to 5-fluorouracil. Thus, rapid injection of floxuridine produces the same toxic and antimetabolic effects as does 5-fluorouracil. The primary effect is to interfere with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibit the formation of ribonucleic acid (RNA). However, when floxuridine is given by continuous intraarterial infusion its direct anabolism to floxuridine-monophosphate is enhanced, thus increasing the inhibition of DNA.

Floxuridine is metabolized in the liver. 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; it is also expired as respiratory carbon dioxide. Pharmacokinetic data on intra-arterial infusion of floxuridine are not available.

Patients should be informed of expected toxic effects, particularly oral manifestations. Patients should be alerted to the possibility of alopecia as a result of therapy and should be informed that it is usually a transient effect.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

FLOXURIDINE - INJECTION

(flox-YOUR-eh-deen)

COMMON BRAND NAME(S): FUDR

USES: Floxuridine is used to treat certain types of stomach/intestinal cancer that have spread to the liver. It is a chemotherapy drug that is used to slow or stop cancer cell growth.

HOW TO USE: This medication is given by injection into an artery using a continuous infusion pump. It is given through a catheter placed inside the artery that supplies blood to the tumor. This method directs the medication to the tumor so that it can have a stronger effect on the tumor with less risk of serious side effects in the rest of the body. When starting the first course of treatment with this medication, you should be in a hospital where you can be monitored for possible serious side effects.

This medication will be prepared and mixed for you by a health care professional. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. If you have any questions about the use of this medication, consult your health care professional.

Dosage is based on your medical condition, weight, and response to treatment.

This medication should be used as long as you continue to benefit from the treatment. When serious side effects appear, your doctor will stop treatment with this medication. After the side effects have lessened, treatment will resume.

SIDE EFFECTS: Nausea, vomiting, mild diarrhea, loss of appetite, tiredness, redness at the injection site, or dry skin may occur. Nausea and vomiting can be severe. In some cases, your doctor may prescribe medication to prevent or relieve nausea and vomiting. Eating several small meals or limiting activity may help lessen some of these effects. If these effects persist or worsen, tell your doctor or pharmacist promptly.

Temporary hair loss may occur. Normal hair growth should return after treatment has ended.

Many people using this medication have some serious side effects. However, your doctor has prescribed this drug because he or she has judged that the benefit to you is greater than the risk of side effects.

This medication can lower the body's ability to fight an infection. Tell your doctor promptly if you develop any signs of an infection such as fever or chills.

Tell your doctor immediately if any of these unlikely but serious side effects occur: mouth sores, sore throat, painful/difficult swallowing, persistent or severe vomiting/diarrhea, easy or unusual bruising/bleeding, black stools, blood/mucus in the stools, vomit that looks like coffee grounds, cramps/pain in the stomach/abdomen, yellowing eyes/skin, dark urine, weakness, weight loss, skin problems (e.g., unusual sunburn, peeling/darkening of the skin), muscle/joint pain.

Seek immediate medical attention if any of these rare but very serious side effects occur: chest/jaw/left arm pain, warmth/swelling/pain/leaking at the injection site, pain/swelling/redness/weakness of the arms or legs, calf pain/swelling that is warm to the touch, shortness of breath, coughing up blood, sudden vision changes, weakness on one side of the body, severe clumsiness/trouble walking, slurred speech, confusion, severe headache.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using floxuridine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: poor nutrition, decreased bone marrow function/blood cell disorders (e.g., anemia, leukopenia, thrombocytopenia), a serious infection.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver problems, kidney problems, past high-dose radiation treatment of the pelvis.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received polio vaccine by mouth or flu vaccine inhaled through the nose.

Since this medication can increase your risk of developing serious infections, wash your hands well to prevent the spread of infections. Avoid contact with people who have illnesses that may spread to others (e.g., flu, chickenpox).

To lower the chance of getting cut, bruised, or injured, use caution with sharp objects like safety razors and nail cutters, and avoid activities such as contact sports.

Although unlikely, this medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

This medication is not recommended for use during pregnancy. It may harm an unborn baby. Consult your doctor for more details and to discuss reliable forms of birth control. It is recommended that men and women use 2 effective forms of birth control (e.g., condoms, birth control pills) while using this medication.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: past or present use of alkylating-type cancer drugs (e.g., chlorambucil, cyclophosphamide, melphalan).

If you are currently using or have used any of these medications listed above, tell your doctor or pharmacist before starting floxuridine.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs that may decrease bone marrow function (e.g., azathioprine, trimethoprim/sulfamethoxazole).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Laboratory and/or medical tests (e.g., complete blood counts) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: It is important that each dose of this medication is given as scheduled. If you miss a dose, contact your doctor to establish a new dosing schedule.

STORAGE: Store the unmixed vials at room temperature between 59-86 degrees F (15-30 degrees C). Once the vials are mixed, if they are not used immediately, they may be stored in the refrigerator between 36-46 degrees F (2-8 degrees C) and should be used or discarded within 2 weeks.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.