5-5-fluorouracil 50 MG/ML Injectable Solution
WARNINGS
THE DAILY DOSE OF FLUOROURACIL IS NOT TO EXCEED 800 MG.
IT IS RECOMMENDED THAT PATIENTS BE HOSPITALIZED DURING THEIR FIRST COURSE OF TREATMENT.
Fluorouracil should be used with extreme caution in poor risk patients with a history of high-dose pelvic irradiation or previous use of alkylating agents, those who have a widespread involvement of bone marrow by metastatic tumors or those with impaired hepatic or renal function.
Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to deficiency of dipyrimidine dehydrogenase activity.
1 A few patients have been rechallenged with 5-fluorouracil and despite 5-fluorouracil dose lowering, toxicity recurred and progressed with worse morbidity.
Absence of this catabolic enzyme appears to result in prolonged clearance of 5-fluorouracil.
Pregnancy Teratogenic Effects – Pregnancy Category D Fluorouracil may cause fetal harm when administered to a pregnant woman.
Fluorouracil has been shown to be teratogenic in laboratory animals.
Fluorouracil exhibited maximum teratogenicity when given to mice as single intraperitoneal injections of 10 to 40 mg/kg on day 10 or 12 of gestation.
Similarly, intraperitoneal doses of 12 to 37 mg/kg given to rats between days 9 and 12 of gestation and intramuscular doses of 3 to 9 mg given to hamsters between days 8 and 11 of gestation were teratogenic.
Malformations included cleft palates, skeletal defects and deformed appendages, paws and tails.
The dosages which were teratogenic in animals are 1 to 3 times the maximum recommended human therapeutic dose.
In monkeys, divided doses of 40 mg/kg given between days 20 and 24 of gestation were not teratogenic.
There are no adequate and well-controlled studies with fluorouracil in pregnant women.
While there is no evidence of teratogenicity in humans due to fluorouracil, 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.
Women of childbearing potential should be advised to avoid becoming pregnant.
If the drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be told of the potential hazard to the fetus.
Fluorouracil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 Fluorouracil.
DRUG INTERACTIONS
Drug Interactions Leucovorin calcium may enhance the toxicity of fluorouracil.
Also see WARNINGS section.
OVERDOSAGE
The possibility of overdosage with fluorouracil 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 overdose of Fluorouracil should be monitored hematologically for at least four weeks.
Should abnormalities appear, appropriate therapy should be utilized.
The acute intravenous toxicity of fluorouracil is as follows: Species LD 50 (mg/kg ±S.E.) Mouse 340 ± 17 Rat 165 ± 26 Rabbit 27 ± 5.1 Dog 31.5 ± 3.8
DESCRIPTION
Fluorouracil Injection, USP an antineoplastic antimetabolite, is a colorless to yellow aqueous sterile, nonpyrogenic injectable solution for intravenous administration.
Each mL contains: 50 mg of fluorouracil; pH is adjusted to approximately 9.2 with sodium hydroxide.
Chemically, fluorouracil, a fluorinated pyrimidine, is 5-fluoro-2,4 (1 H ,3 H )-pyrimidinedione.
It is a white to practically white crystalline powder which is sparingly soluble in water.
The molecular weight is 130.08 and the structural formula is: C 4 H 3 FN 2 O 2 .
A pharmacy bulk package is a container of a sterile preparation for parenteral use that contains many single doses.
The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion or the filling of empty sterile syringes for patients with individualized dosing requirements.
Chemical Structure
HOW SUPPLIED
NDC 66758-054-01: 50 mg/mL in a 50 mL flip-top Pharmacy Bulk Package vial, individually packaged.
NDC 66758-054-02: 50 mg/mL in a 100 mL flip-top Pharmacy Bulk Package vial, individually packaged.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
DO NOT FREEZE.
PROTECT FROM LIGHT .
Vial stoppers do not contain natural rubber latex.
For Sandoz Inc.
Customer Service, call 1-800-525-8747.
Manufactured for: SANDOZ Princeton, NJ 08540 Manufactured by: Ebewe PHARMA A-4866 Unterach, AUSTRIA April 2011
INDICATIONS AND USAGE
Fluorouracil is effective in the palliative management of carcinoma of the colon, rectum, breast, stomach and pancreas.
PEDIATRIC USE
Pediatric Use Safety and effectiveness in children have not been established.
PREGNANCY
Pregnancy Teratogenic Effects – Pregnancy Category D Fluorouracil may cause fetal harm when administered to a pregnant woman.
Fluorouracil has been shown to be teratogenic in laboratory animals.
Fluorouracil exhibited maximum teratogenicity when given to mice as single intraperitoneal injections of 10 to 40 mg/kg on day 10 or 12 of gestation.
Similarly, intraperitoneal doses of 12 to 37 mg/kg given to rats between days 9 and 12 of gestation and intramuscular doses of 3 to 9 mg given to hamsters between days 8 and 11 of gestation were teratogenic.
Malformations included cleft palates, skeletal defects and deformed appendages, paws and tails.
The dosages which were teratogenic in animals are 1 to 3 times the maximum recommended human therapeutic dose.
In monkeys, divided doses of 40 mg/kg given between days 20 and 24 of gestation were not teratogenic.
There are no adequate and well-controlled studies with fluorouracil in pregnant women.
While there is no evidence of teratogenicity in humans due to fluorouracil, 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.
Women of childbearing potential should be advised to avoid becoming pregnant.
If the drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be told of the potential hazard to the fetus.
Fluorouracil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NUSRING MOTHERS
Nursing Mothers It is not known whether fluorouracil is excreted in human milk.
Because fluorouracil inhibits DNA, RNA and protein synthesis, mothers should not nurse while receiving this drug.
BOXED WARNING
PHARMACY BULK PACKAGE – Not For Direct Infusion WARNING It is recommended that FLOUROURACIL be given only by or under the supervision of a qualified physician who is experienced in cancer chemotherapy and who is well versed in the use of potent antimetabolites.
Because of the possibility of severe toxic reactions, it is recommended that patients be hospitalized at least during the initial course of therapy.
INFORMATION FOR PATIENTS
Information for Patients 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.
DOSAGE AND ADMINISTRATION
General Instructions Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.
No dilution is required.
All dosages are based on the patient’s actual weight.
However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.
It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.
Dosage 12 mg/kg are given intravenously once daily for 4 successive days.
The daily dose should not exceed 800 mg.
If no toxicity is observed , 6 mg/kg are given on the 6 th , 8 th , 10 th and 12 th days unless toxicity occurs .
No therapy is given on the 5 th , 7 th , 9 th or 11 th days.
Therapy is to be discontinued at the end of the 12 th day, even if no toxicity has become apparent.
(See WARNINGS and PRECAUTIONS .) Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.
If no toxicity is observed , 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.
No therapy is given on the 4 th , 6 th or 8 th days.
The daily dose should not exceed 400 mg.
A sequence of injections on either schedule constitutes a “course of therapy.” Maintenance Therapy In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules: 1.
Repeat dosage of first course every 30 days after the last day of the previous course of treatment.
2.
When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.
Do not exceed 1 gm per week.
The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.
Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.
Procedures for proper handling and disposal of anticancer drugs should be considered.
Several guidelines on this subject have been published.
2-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropiate.
Note Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.
If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.
DIRECTION FOR PROPER USE OF PHARMACY BULK PACKAGE Pharmacy Bulk Packages are for use in a Pharmacy Admixture Service only in a vertical laminar flow hood.
The container closure should be penetrated only one time utilizing a suitable sterile dispensing set or transfer device which allows measured distribution of the contents.
Swab vial stopper with an antiseptic solution.
Insert the device/set into the vial using aseptic technique.
Once the sterile dispensing set or transfer device has been inserted into the container, withdrawal of the contents should be accomplished without delay.
However, if this is not possible, a maximum time of 4 hours from the initial entry may be allowed to complete fluid aliquoting/transferring operations.
The transferred drug solution should be used promptly.
Discard the contents no later than 4 hours after initial closure puncture.