Full Prescribing Info
Each mL solution for injection contains: Fluorouracil 50 mg.
5-FU is used for the treatment of the following malignancies: Carcinoma of the colon or rectum (Colorectal carcinoma): Alone or in combination with leucovorin for the treatment of advanced colorectal cancer.
Breast cancer: In combination chemotherapy as an adjunct to surgery in women with breast cancer.
5-FU has also shown activity in the following malignancies: Gastric cancer.
Primary hepatic cancer.
Pancreatic cancer.
Uterine (particularly cervical) cancer.
Ovarian cancer.
Bladder cancer.
Dosage/Direction for Use
General Directions: 5-FU may be given by IV injection or IV infusion with the latter usually being preferred because of lesser toxicity. Care should be taken to avoid extravasation of the drug. The drug may be administered through a 25-gauge needle.
5-FU (Fucil) does not contain any antimicrobial agent. When used for infusion, 5-FU should be used immediately after dilution. The product is for single use in one patient only. Any residue should be discarded according to the guidelines for the disposal and handling of cytotoxic drugs (see Special Handling Precautions under Cautions for Usage).
The dose of 5-FU is based on the patient's actual weight unless the patient is obese or has fluid retention. In these latter instances, dose is based on ideal weight. Dosage can also be calculated according to body surface area. Dose 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 and the method and sequence of administration of 5-FU and other chemotherapeutic agents.
Usual Adult Dose: As IV Injection: Initial course: 5-FU 12 mg/kg body weight once a day for 4 consecutive days.
If no toxic manifestations are observed, 6 mg/kg body weight is given on days 6, 8, 10, and 12 unless a toxic reaction occurs before then (no therapy is given on days 5, 7, 9, and 11).
The daily dose should not exceed 800 mg in this regimen.
Discontinue on day 12 even if no toxicity has become apparent.
An alternative regimen is 15 mg/kg body weight as a single IV injection once a week throughout the course.
As IV Infusion: 5-FU 15 mg/kg body weight (but not more than 1 g per infusion) diluted in 500 mL of 0.9% sodium chloride or 5% dextrose given once a day at a rate of 40 drops per minute over a period of 4 hours.
The infusion may be repeated on successive days until the first GI side effects (stomatitis and diarrhea) or hematological side effects (e.g., leukopenia or thrombocytopenia) appear or a total of 12 to 15 g has been given.
Alternatively, the daily dose may be infused over 30 to 60 minutes or may be given as a continuous IV infusion over 24 hours.
As Intra-arterial Infusion: 5-FU 5 to 7.5 mg/kg body weight per day may be administered as a 24-hour intra-arterial continuous drip infusion.
Maintenance Therapy: For patients in whom toxicity has not been a problem, the initial therapy should be repeated at intervals of 30 days after the last dose of the previous course.
Alternatively, when toxicity from the initial course of therapy has subsided, a single weekly maintenance of 10 to 15 mg/kg may be administered; weekly maintenance dose should not exceed 1 g.
The dosage schedule to be used in repeated courses depends on the patient's reaction to the previous course and should be adjusted accordingly.
Combination Therapy with Leucovorin: Commonly employed regimen: 5-FU by IV injection at a dose of 370 to 400 mg/m2 (9 to 10 mg/kg body weight) for 5 days after administration of leucovorin 200 to 500 mg/m2 (5 to 12 mg/kg body weight) for 5 days. Repeat course every 4 weeks.
The patient should be monitored for toxic signs. Drug therapy should be appropriately adjusted or discontinued if toxic signs such as GI bleeding manifest.
Recommendations for Poor Risk Patients: As IV Injection: Initial IV course of 5-FU 240 mg/m2 (6 mg/kg body weight) once a day for 3 days.
If no toxic manifestations are observed, 5-FU 3 mg/kg body weight is given on days 5, 7 and 9 unless a toxic reaction occurs before then.
The daily dose should not exceed 400 mg.
Repeat course every 30 days.
As IV Infusion: 5-FU 240 mg/m2 (6 mg/kg body weight) diluted in 500 mL of 0.9% sodium chloride or 5% dextrose given once a day over a period of 4 hours, until signs of toxicity are observed, usually within 8 to 15 days.
Renal and Hepatic Impairment: 5-FU should be used with caution in patients with renal or hepatic impairment. Dose adjustment appropriate to the degree of impairment and to the reaction of the patient to the previous 5-FU course should be taken into account.
Treatment with 5-FU should be discontinued promptly whenever any of the following signs of toxicity appears: Stomatitis or esophagopharyngitis, at the first visible sign.
Leukocyte count falls below 3500/mm3 or decreases rapidly.
Platelet count falls below 100,000/mm3.
Granulocyte count falls below 1500/mm3.
Intractable vomiting.
Diarrhea, frequent bowel movements or watery stools.
GI ulceration or bleeding.
Hemorrhage at any site.
Central or peripheral nervous system toxicity, including ataxia and tremor.
Cardiac toxicity.
Dosage Reduction in Combination Therapy: When 5-FU is combined with other antineoplastics of similar toxicity profile or with radiotherapy, the recommended dosage should be adjusted accordingly.
Hypersensitivity to 5-FU or any ingredient of the product.
Poor nutritional state.
Dihydropyrimidine dehydrogenase enzyme deficiency.
Depressed bone marrow function (generally a leukocyte count of ≤5000/mm3 and/or a platelet count of ≤100,000/m3).
Potentially serious infections.
Pregnant or breastfeeding women.
Management of non-malignant disease.
Special Precautions
5-FU is a potent drug and should be prescribed only by physicians experienced with cancer chemotherapeutic drugs. Blood counts as well as renal and hepatic function tests should be performed regularly. Discontinue the drug if there is significant leukopenia (under 3500/mm3) or granulocytopenia (under 1500/mm3).
GI Effects: Anorexia and nausea are common adverse effects of 5-FU and vomiting occurs frequently. These reactions generally occur during the first week of therapy, can often be alleviated by antiemetics and generally subside within 2 or 3 days following therapy. Stomatitis is one of the most common and often the earliest sign of specific toxicity, appearing as early as the 4th day but more commonly on the 5th to 8th day of therapy. Diarrhea, which also occurs frequently, usually appears slightly later than stomatitis, but may occur more concurrently or even in the absence of stomatitis. Patients should be questioned and the mouth examined daily for early evidence of stomatitis. Appearance of stomatitis, as evidenced by either oral mucosal erythema or ulceration at the inner margin of the lips, or of esophagopharyngitis as evidenced by sore throat or dysphagia, necessitates cessation of therapy.
Hematologic Effects: Leukopenia (predominantly granulocytopenia), thrombocytopenia and anemia occur commonly with 5-FU therapy; leukopenia usually occurs after an adequate course of 5-FU therapy. The nadir of the white blood cell count usually occurs from the 9th to the 14th day after therapy is initiated but may occur as late as the 25th day after the first dose of 5-FU; counts usually return to normal after about 30 days. Maximum thrombocytopenia has been reported to occur from the 7th to 17th day of therapy. Hematopoietic recovery is usually rapid and by the 13th day, blood cell counts have usually reached the normal range.
Leukocyte counts with differential should be made before each dose of 5-FU is given. If the leukocyte count drops to < 2000/mm3, the patient should be placed in protective isolation and appropriate measures taken for the prevention of infection. During maintenance therapy, counts before each course are sufficient.
Cardiac Effects: 5-FU should not be readministered after a documented cardiovascular reaction (arrhythmia, angina, ST segment changes) as there is a risk of sudden death. 5-FU should be used with caution in patients who experience chest pain during courses of treatment of those with heart disease.
Neurological Effects: In cases of severe neurological toxicity, continued treatment with 5-FU is not recommended (see Adverse Reactions).
Effects on the Ability to Drive and Use Machines: 5-FU may induce nausea and vomiting which could interfere with driving or the use of heavy machinery.
Other Populations: 5-FU should be used with extreme caution and the initial dose may be reduced by one-third to one-half in the following patients: Undergone recent major surgery (within previous 30 days).
Patients who have previously received high-dose irradiation therapy to bone marrow-bearing areas (pelvis, spine, ribs, etc.) or alkylating agents.
Impaired hepatic or renal function (see Dosage & Administration).
History of heart disease (see Precautions).
Widespread metastatic involvement of the bone marrow.
Patients who are known or suspected to have a dihydropyrimidine dehydrogenase deficiency.
Carcinogenicity, Mutagenicity and Impairment of Fertility: Carcinogenicity: Long-term studies in animals to determine the carcinogenic potential of 5-FU have not been performed; however, no evidence of carcinogenicity was observed in several animal studies following oral or IV administration of the drug for up to 1 year. In vitro, the drug has induced oncogenic transformation of fibroblasts from mouse embryo. The carcinogenic risk in humans is not known.
Mutagenicity: 5-FU has been shown to be mutagenic and clastogenic in a number of studies. In addition, the drug was mutagenic in the micronucleus test on mouse bone marrow cells and at very high concentrations, produced chromosomal breaks in hamster fibroblasts in vitro. Although the risk of mutagenesis in patients receiving 5-FU has not been evaluated, the possibility must be considered.
Impairment of Fertility: 5-FU has not been adequately studied in animals to determine the effects on fertility and general reproductive performance. Following intraperitoneal administration of 125 or 250 mg/kg in rats, chromosomal aberrations and changes in chromosomal organization of spermatogonia were induced; spermatogonial differentiation was also inhibited, resulting in transient infertility. In a strain of mouse that is insensitive to the induction of sperm head abnormalities after exposure to a number of chemical mutagens and carcinogens, no abnormalities were produced at oral dosages of up to 80 mg/kg daily. Following intraperitoneal administration at weekly doses of up to 25 or 50 mg/kg for 3 weeks during the preovulatory phases of oogenesis in female rats, the incidence of female matings was substantially reduced, development of preimplantation and postimplantation embryos was delayed, and the incidence of preimplantation lethality and chromosomal anomalies in the embryo was increased. In a limited study in rabbits, a single 25 mg/kg dose or daily doses of 5 mg/kg for 5 days had no effect on ovulation, appeared not to affect implantation, and had only a limited effect in producing zygote destruction. Drugs that inhibit DNA, RNA and protein synthesis such as 5-FU may have adverse effects on gametogenesis.
Use in Children: The safety and efficacy of 5-FU in children have not been established.
Use in Elderly: 5-FU should be used with caution in elderly patients. An age of 70 years or older and the female gender are reported independent risk factors for severe toxicity from 5-FU-based chemotherapy. These effects may be additive in older women. Close monitoring for multiple organ toxicities and vigorous supportive care from those with toxicity are necessary.
Use In Pregnancy & Lactation
Use in Pregnancy: Pregnancy Category D: 5-FU may cause fetal harm when administered to pregnant women. Although it is not known whether 5-FU crosses the human placenta, it has been shown to cross the placenta and enter fetal circulation in rats. In monkeys, doses greater than 40 mg/kg resulted in abortion of all embryos exposed to the drug. Although there is no evidence to date of teratogenicity caused by 5-FU in humans, other drugs that inhibit DNA synthesis (e.g., methotrexate) have been reported to be teratogenic in humans; in addition, drugs that inhibit DNA, RNA and protein synthesis such as 5-FU may have adverse effects on perinatal and postnatal development. 5-FU should not be used in pregnancy.
Use in Lactation: It is not known whether 5-FU is distributed into milk. Because 5-FU inhibits DNA, RNA and protein synthesis, it is recommended that women do not breastfeed an infant while receiving the drug.
Adverse Reactions
Therapeutic response is unlikely to occur without some evidence of toxicity. The major toxic effects of 5-FU are on the normal, rapidly proliferating tissues particularly of the bone marrow and lining of the GI tract. Toxicity is schedule-dependent: reducing the rate of injection to a slow infusion is associated with less hematological toxicity but does not decrease GI toxicity.
GI Effects: Anorexia, nausea and vomiting are common. Stomatitis and esophagopharyngitis are common signs of toxicity. Esophagitis, proctitis, GI ulceration and bleeding have been reported, and paralytic ileus occurred in two patients who received excessive doses.
Hematologic Effects: Leukopenia (predominantly granulocytopenia), thrombocytopenia and anemia are common. Pancytopenia, agranulocytosis and hemolytic anemia have also occurred. Leukopenia and thrombocytopenia may be less frequent during maintenance therapy.
Hypersensitivity Reactions: Allergic reactions including anaphylaxis, bronchospasm, urticaria, and pruritus have been reported. If anaphylactic shock occurs, the usual countermeasures should be employed.
Dermatologic Effects: Hair loss occurs frequently with 5-FU therapy, and cosmetically significant alopecia has occurred in a substantial number of patients. Regrowth of hair has been reported even in patients receiving repeated courses of the drug. Partial loss of nails has occurred rarely, and diffuse melanosis of the nails has been reported. The most common type of dermatologic toxicity is a pruritic maculopapular rash which usually appears on the extremities and less frequently on the trunk. This rash is generally reversible and usually responsive to symptomatic treatment.
An erythematous, desquamative rash involving the hands and feet has been reported in patients receiving 5-FU (in some cases, prolonged infusions of high doses of the drug were administered). The rash may be accompanied by tingling of painful hands and feet, swollen palms and soles and phalangeal tenderness. These adverse effects, referred to as palmar-plantar erythrodysesthesia or hand-foot syndrome, may gradually disappear over 5 to 7 days after discontinuance of 5-FU therapy.
Other dermatologic manifestations of 5-FU toxicity have included dry skin and fissuring, diffuse erythema and scaling. Exposure to strong sunlight may intensify skin reactions to the drug. Seborrheic dermatitis has been reported in a few patients, but could not always be definitely attributed to 5-FU. Recall phenomenon and photosensitivity manifested by erythema or increased pigmentation can occur with 5-FU therapy.
Neurological Effects: Disorientation, confusion, euphoria, ataxia, dysarthria, nystagmus, headache, slurred speech, dizziness, unsteadiness, muscular weakness, vertigo, Parkinson-like symptoms, pyramid signs, aphasia, convulsions, coma, optic neuritis, peripheral neuropathy and acute cerebellar syndrome (which may persist after therapy is discontinued) have occurred rarely in patients receiving 5-FU. Oculomotor disturbances have occurred occasionally. Extrapyramidal or cortical dysfunction (usually reversible) and isolated cases of leucoencephalopathy have also been reported. These symptoms may persist after therapy is discontinued.
Ocular Effects: Conjunctivitis was commonly reported. Excessive lacrimation, dacryostenosis, visual changes, photophobia, diplopia, blepharitis, and ectropion have been uncommon. Lacrimal duct stenosis (canalicular fibrosis) associated with prolonged administration of 5-FU has been rarely reported. This condition is reversible upon reduction or temporary cessation of 5-FU therapy, but on occasion may necessitate surgical intervention.
Cardiovascular Effects: There have been reports of chest pain, tachycardia, breathlessness, ECG changes (ST segment changes), myocardial ischemia, angina (including Prinzmetal variant angina), precordial pain, cardiac arrhythmias, dilatative cardiomyopathy, ischemia and heart failure resulting rarely in death. Vasculitis, Raynaud's phenomenon and thromboembolism have been rarely reported.
Hepatic Effects: Hepatocellular damage and in very rare cases, fatal hepatic necrosis have been observed.
Infection: Due to immunosuppression, infections (sometimes serious), may develop in patients treated with 5-FU. Sepsis was uncommon.
Others: Fever that occurred during the end of the 2nd week following the first dose of 5-FU, and was usually not accompanied by demonstrable infection, has been reported. Epistaxis, thrombophlebitis, vein pigmentation, and dehydration have also been reported. Hyperuricemia was uncommon.
Drug Interactions
Nucleoside Analogues (e.g., Brivudin and Sorivudine): The enzyme dihydropyrimidine dehydrogenase plays an important role in the degradation of 5-FU. Nucleoside analogues can cause a sharp rise in plasma concentrations of 5-FU and other fluoropyrimidines, with accompanying toxic reactions (e.g., severe leukopenia). A period of 4 weeks should elapse between the administration of 5-FU and nucleoside analogues. Where applicable, determination of dihydropyrimidine dehydrogenase enzyme activity is indicated before starting treatment with 5-fluoropyrimidines.
Cimetidine: Pretreatment with cimetidine for 4 weeks may increase plasma concentrations of 5-FU by 27%. The total body clearance was reduced by 28%. This may lead to increased plasma concentrations of 5-FU.
Clozapine: Concomitant administration with 5-FU should be avoided due to the increased risk of agranulocytosis.
Interferon alfa-2b: Concomitant administration with 5-FU has produced a marked increase in the initial plasma concentration of 5-FU and a decrease in 5-FU clearance.
Leucovorin: Leucovorin and 5-FU are routinely used together in the treatment of colorectal cancer due to their synergistic effect. Leucovorin is metabolized to a reduced folate co-factor that is necessary for maximal inhibition of thymidylate synthetase by Fd-UMP, the active metabolite of 5-FU. Leucovorin enhances the DNA-directed toxicity of 5-FU. This combination should be used with caution since leucovorin may exacerbate the GI toxicity of 5-FU.
Levamisole: Combination therapy with 5-FU has been associated with multifocal inflammation leucoencephelopathy (MILE). Symptoms may include memory loss, confusion, paresthesia, muscle weakness, speech disturbances, coma, and seizures. The CSF may show mild pleiocytosis, and computed tomography and magnetic resonance scans may show lesions in the white matter suggestive of demyelination. If this syndrome occurs, treatment should be discontinued immediately. The condition as at least partially reversible if 5-FU and levamisole are discontinued and corticosteroids are given.
Methotrexate: Administration of methotrexate followed by 5-FU leads to a synergistic interaction in the treatment of head and neck, breast and colorectal cancers. Biochemical modulation may occur through effects on RNA and DNA synthesis and enhancement of 5-FU uptake. The importance of time interval between methotrexate and 5-FU exposure in the treatment of metastatic colon cancer has been demonstrated. When these two agents are separated by 24 hours as compared with 1 hour, the response rate, time to progression and survival are significantly improved. However, different tumors may respond differently to changes in the time interval between methotrexate and 5-FU. 5-FU preceded by methotrexate has been demonstrated to double the response rate to 5-FU in metastatic colorectal cancer and produce survival benefits.
Metronidazole: Has been shown to reduce the clearance of 5-FU and increase its toxicity in colorectal cancer patients.
Mitomycin: Hemolytic-uremic syndrome has been reported to occur after long-term use of 5-FU in combination with mitomycin.
Phenytoin: Patients taking phenytoin concomitantly with 5-FU should undergo regular testing because of the possibility of elevated plasma levels of phenytoin resulting in symptoms of phenytoin toxicity.
Sorafenib: Has been reported to have variable effects on 5-FU.
Warfarin: Marked elevations of prothrombin time and INR have been reported in a few patients stabilized on warfarin therapy following initiation of 5-FU regimens.
Laboratory Test Alterations: Increase in or false positive results may be observed in tests for bilirubin (icteric index) and 5-hydroxyindole acetic acid in the urine. 5-FU could interfere with diagnostic tests of thyroid function by causing rises in total thyroxine and liothyronine due to increased globulin binding. Plasma albumin may be decreased because of drug-induced protein malabsorption.
ATC Classification
L01BC02 - fluorouracil ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.
Soln for inj/infusion (vial) 500 mg/10 mL x 1's.
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