Fluorouracil Information
Fluorouracil ()
Fluorouracil () 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 (1,3)-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:
CHFNO.
A 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.
Fluorouracil () Clinical Pharmacology
There is evidence that the metabolism of Fluorouracil () in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid. In this manner, Fluorouracil () interferes with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibits the formation of ribonucleic acid (RNA). Since DNA and RNA are essential for cell division and growth, the effect of Fluorouracil () may be to create a thymine deficiency which provokes unbalanced growth and death of the cell. The effects of DNA and RNA deprivation are most marked on those cells which grow more rapidly and which take up Fluorouracil () at a more rapid rate.
Following intravenous injection, Fluorouracil () distributes into tumors, intestinal mucosa, bone marrow, liver and other tissues throughout the body. In spite of its limited lipid solubility, Fluorouracil () diffuses readily across the blood-brain barrier and distributes into cerebrospinal fluid and brain tissue.
Seven to 20 percent of the parent drug is excreted unchanged in the urine in 6 hours; of this, over 90% is excreted in the first hour. The remaining percentage of the administered dose is metabolized, primarily in the liver. The catabolic metabolism of Fluorouracil () results in degradation products (, CO, urea and α-fluoro-β-alanine) which are inactive. The inactive metabolites are excreted in the urine over the next 3 to 4 hours. When Fluorouracil () is labeled in the six carbon position, thus preventing the C metabolism to CO, approximately 90% of the total radioactivity is excreted in the urine. When Fluorouracil () is labeled in the two carbon position approximately 90% of the total radioactivity is excreted in expired CO. Ninety percent of the dose is accounted for during the first 24 hours following intravenous administration.
Following intravenous administration of Fluorouracil () , the mean half-life of elimination from plasma is approximately 16 minutes, with a range of 8 to 20 minutes, and is dose dependent. No intact drug can be detected in the plasma 3 hours after an intravenous injection.
Fluorouracil () Indications And Usage
Fluorouracil () is effective in the palliative management of carcinoma of the colon, rectum, breast, stomach and pancreas.
Fluorouracil () Contraindications
Fluorouracil () therapy is contraindicated for patients in a poor nutritional state, those with depressed bone marrow function, those with potentially serious infections or those with a known hypersensitivity to Fluorouracil () .
Fluorouracil () 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. 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 () .
Fluorouracil () Precautions
Fluorouracil () 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 Fluorouracil () 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:
The administration of 5-Fluorouracil () has been associated with the occurrence of palmar-plantar erythrodysesthesia syndrome, also known as hand-foot syndrome. This syndrome has been characterized as a tingling sensation of hands and feet which progress over the next few days to pain when holding objects or walking. The palms and soles became symmetrically swollen and erythematous with tenderness of the distal phalanges, possibly accompanied by desquamation. Interruption of therapy is followed by gradual resolution over 5 to 7 days. Although pyridoxine has been reported to ameliorate the palmarplantar erythrodysesthesia syndrome, its safety and effectiveness has not been established.
Leucovorin calcium may enhance the toxicity of Fluorouracil () .
Also see section.
Fluorouracil () Adverse Reactions
Stomatitis and esophagopharyngitis (which may lead to sloughing and ulceration), diarrhea, anorexia, nausea and emesis are commonly seen during therapy.
Leukopenia usually follows every course of adequate therapy with Fluorouracil () . The lowest white blood cell counts are commonly observed between the 9 and 14 days after the first course of treatment, although uncommonly the maximal depression may be delayed for as long as 20 days. By the 30th day the count has usually returned to the normal range.
Alopecia and dermatitis may be seen in a substantial number of cases. The dermatitis most often seen is a pruritic maculopapular rash usually appearing on the extremities and less frequently on the trunk. It is generally reversible and usually responsive to symptomatic treatment.
Other adverse reactions are:
Fluorouracil () 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:
Fluorouracil () Dosage And Administration
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 () .
In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:
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. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropiate.
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.
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.
Fluorouracil () How Supplied
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: Princeton, NJ 08540
Manufactured by: PHARMAA-4866 Unterach, AUSTRIA
April 2011
Fluorouracil () Principal Display Panel- Ml Vial Label
NDC 66758-054-0150 mL Vial
