Fluorouracil is indicated for the treatment of patients with: Fluorouracil is a nucleoside metabolic inhibitor indicated for the treatment of patients with Adenocarcinoma of the Colon and Rectum (1.1) Adenocarcinoma of the Breast (1.2) Gastric Adenocarcinoma (1.3) Pancreatic Adenocarcinoma (1.4) 1.1. Adenocarcinoma of the Colon and Rectum . 1.2. Adenocarcinoma of the Breast . 1.3. Gastric Adenocarcinoma . 1.4. Pancreatic Adenocarcinoma .
Contraindications
None. None
Warnings and precautions
Increased Risk of Serious or Fatal Adverse Reactions in Patients with Low or Absent Dipyrimidine Dehydrogenase Activity: Withhold or permanently discontinue fluorouracil in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of dipyrimidine dehydrogenase (DPD) activity. No fluorouracil dose has been proven safe in patients with absent DPD activity.
(5.1) Cardiotoxicity: Fluorouracil can cause cardiotoxicity, including angina, myocardial infarction/ischemia, arrhythmia, and heart failure. Withhold fluorouracil for cardiac toxicity. (5.2) Hyperammonemic Encephalopathy: Altered mental status, confusion, disorientation, coma, or ataxia with elevated serum ammonia level can occur within 72 hours of initiation of fluorouracil. Withhold fluorouracil and initiate ammonia-lowering therapy.
(5.3) Neurologic Toxicity: Fluorouracil can cause acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances. Withhold fluorouracil for neurologic toxicity. (5.4) Diarrhea: Fluorouracil can cause severe diarrhea. Withhold fluorouracil for severe diarrhea until resolved. (5.5) Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome): Fluorouracil can cause hand-foot syndrome. If severe, discontinue fluorouracil until resolved or decreased to Grade 1, then resume at a reduced dose.
(5.6) Myelosuppression: Fluorouracil can cause severe and fatal myelosuppression. Withhold fluorouracil until severe myelosuppression resolves, then resume at a reduced dose. (5.7) Mucositis: Fluorouracil can cause severe mucositis. Discontinue fluorouracil until resolved or decreased to Grade 1, then resume at a reduced dose. (5.8) Increased Risk of Elevated INR with Warfarin: Concurrent administration with warfarin can result in clinically significant increases in coagulation parameters: Closely monitor INR and prothrombin time.(5.9) Embryofetal Toxicity: Fluorouracil can cause fetal harm.
Two medicines in one question?
Name two or more medicines and Osler runs an interaction check. A severe interaction is stated at the very top of the answer.
Advise females and males of reproductive potential of the potential risk to a fetus. (5.10, 8.1, 8.6) 5.1. Increased Risk of Serious or Fatal Adverse Reactions in Patients with Low or Absent Dipyrimidine Dehydrogenase (DPD) Activity Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by fluorouracil (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity).
Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by fluorouracil. Withhold or permanently discontinue fluorouracil based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity.
No fluorouracil dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test. 5.2. Cardiotoxicity Fluorouracil can cause cardiotoxicity, including angina, myocardial infarction/ischemia, arrhythmia, and heart failure, based on postmarketing reports. Reported risk factors for cardiotoxicity are administration by continuous infusion rather than intravenous bolus and presence of coronary artery disease.
Withhold fluorouracil for cardiotoxicity. The risks of resumption of fluorouracil in patients with cardiotoxicity that has resolved have not been established. 5.3. Hyperammonemic Encephalopathy Fluorouracil can cause hyperammonemic encephalopathy in the absence of liver disease or other identifiable cause, based on postmarketing reports. Signs or symptoms of hyperammonemic encephalopathy began within 72 hours after initiation of fluorouracil infusion; these included altered mental status, confusion, disorientation, coma, or ataxia, in the presence of concomitant elevated serum ammonia level.
Withhold fluorouracil for hyperammonemic encephalopathy and initiate ammonia-lowering therapy. The risks of resumption of fluorouracil in patients with hyperammonemic encephalopathy that has resolved have not been established. 5.4. Neurologic Toxicity Fluorouracil can cause neurologic toxicity, including acute cerebellar syndrome and other neurologic events, based on postmarketing reports. Neurologic symptoms included confusion, disorientation, ataxia, or visual disturbances.
Withhold fluorouracil for neurologic toxicity. There are insufficient data on the risks of resumption of fluorouracil in patients with neurologic toxicity that has resolved. 5.5. Diarrhea Fluorouracil can cause severe diarrhea. Withhold fluorouracil for Grade 3 or 4 diarrhea until resolved or decreased in intensity to Grade 1, then resume fluorouracil at a reduced dose. Administer fluids, electrolyte replacement, or antidiarrheal treatments as necessary. 5.6.
Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome) Fluorouracil can cause palmar-plantar erythrodysesthesia, also known as hand-foot syndrome (HFS). Symptoms of HFS include a tingling sensation, pain, swelling, and erythema with tenderness, and desquamation. HFS occurs more commonly when fluorouracil is administered as a continuous infusion than when fluorouracil is administered as a bolus injection, and has been reported to occur more frequently in patients with previous exposure to chemotherapy.
HFS is generally observed after 8-9 weeks of fluorouracil administration but may occur earlier. Institute supportive measures for symptomatic relief of HFS. Withhold fluorouracil administration for Grade 2 or 3 HFS; resume fluorouracil at a reduced dose when HFS is completely resolved or decreased in severity to Grade 1. 5.7. Myelosuppression Fluorouracil can cause severe and fatal myelosuppression which may include neutropenia, thrombocytopenia, and anemia.
The nadir in neutrophil counts commonly occurs between 9 and 14 days after fluorouracil administration. Obtain complete blood counts prior to each treatment cycle, weekly if administered on a weekly or similar schedule, and as needed. Withhold fluorouracil until Grade 4 myelosuppression resolves; resume fluorouracil at a reduced dose when myelosuppression has resolved or improved to Grade 1 in severity. 5.8. Mucositis Mucositis, stomatitis or esophagopharyngitis, which may lead to mucosal sloughing or ulceration, can occur with fluorouracil.
The incidence is reported to be higher with administration of fluorouracil by intravenous bolus compared with administration by continuous infusion. Withhold fluorouracil administration for Grade 3 or 4 mucositis; resume fluorouracil at a reduced dose once mucositis has resolved or decreased in severity to Grade 1. 5.9. Increased Risk of Elevated International Normalized Ratio (INR) with Warfarin Clinically significant elevations in coagulation parameters have been reported during concomitant use of warfarin and fluorouracil.
Closely monitor patients receiving concomitant coumarin-derivative anticoagulants such as warfarin for INR or prothrombin time in order to adjust the anticoagulant dose accordingly [see Drug Interactions (7)] . 5.10. Embryofetal Toxicity Based on its mechanism of action, fluorouracil can cause fetal harm when administered to a pregnant woman. In animal studies, administration of fluorouracil at doses lower than a human dose of 12 mg/kg caused teratogenicity.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for 3 months following cessation of therapy
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Interactions
7.1. Anticoagulants and CYP 2C9 Substrates Elevated coagulation times have been reported in patients taking fluorouracil concomitantly with warfarin. While pharmacokinetic data are not available to assess the effect of fluorouracil administration on warfarin pharmacokinetics, the elevation of coagulation times that occurs with the fluorouracil prodrug capecitabine is accompanied by an increase in warfarin concentrations.
Thus, the interaction may be due to inhibition of cytochrome P450 2C9 by fluorouracil or its metabolites.
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Category D Risk Summary
There are no adequate and well-controlled studies with fluorouracil in pregnant women. Based on its mechanism of action, fluorouracil can cause fetal harm when administered to a pregnant woman. Administration of fluorouracil to rats and mice during selected periods of organogenesis, at doses lower than a human dose of 12 mg/kg, caused embryolethality and teratogenicity. Malformations included cleft palate and skeletal defects.
In monkeys, maternal doses of fluorouracil higher than an approximate human dose of 12 mg/kg resulted in abortion. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Clinical Pharmacology (12.1)]. Animal Data Malformations including cleft palate, skeletal defects and deformed appendages (paws and tails) were observed when fluorouracil was administered by intraperitoneal injection to mice at doses at or above 10 mg/kg (approximately 0.06 times a human dose of 12 mg/kg on a mg/m 2 basis) for 4 days during the period of organogenesis.
Similar results were observed in hamsters administered fluorouracil intramuscularly at doses lower than those administered in commonly used clinical treatment regimens. In rats, administration of fluorouracil by intraperitoneal injection at doses greater than 15 mg/kg (approximately 0.2 times a human dose of 12 mg/kg on a mg/m 2 basis) for a single day during organogenesis resulted in delays in growth and malformations including micro-anophthalmos.
In monkeys, administration of fluorouracil during organogenesis at doses approximately equal to a human dose of 12 mg/kg on a mg/m 2 basis resulted in abortion; at a 50% lower dose, resorptions and decreased fetal body weights were reported.
Adverse reactions
The following adverse reactions are discussed in more detail in other sections of the labeling: Increased risk of serious or fatal adverse reactions in patients with low or absent dipyrimidine dehydrogenase activity [see Warnings and Precautions (5.1)] Cardiotoxicity [see Warnings and Precautions (5.2)] Hyperammonemic encephalopathy [see Warnings and Precautions (5.3)] Neurologic toxicity [see Warnings and Precautions (5.4)] Diarrhea [see Warnings and Precautions (5.5)] Palmar-plantar erythrodysesthesia (hand-foot syndrome) [see Warnings and Precautions (5.6)] Myelosuppression [see Warnings and Precautions (5.7)] Mucositis [see Warnings and Precautions (5.8)] Increased risk of elevated INR when administrated with warfarin [see Warnings and Precautions (5.9)] To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals, Inc. at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.2.
Postmarketing Experience The following adverse reactions have been identified during postapproval use of fluorouracil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hematologic: pancytopenia [see Warnings and Precautions (5.7)] Gastrointestinal: gastrointestinal ulceration, nausea, vomiting Allergic Reactions: anaphylaxis and generalized allergic reactions Neurologic: nystagmus, headache Dermatologic: dry skin; fissuring; photosensitivity, as manifested by erythema or increased pigmentation of the skin; vein pigmentation Ophthalmic: lacrimal duct stenosis, visual changes, lacrimation, photophobia Psychiatric: euphoria Miscellaneous: thrombophlebitis, epistaxis, nail changes (including loss of nails)
Composition
Active ingredients
FLUOROURACIL 5GM/100ML (50MG/ML)
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
