Fluorouracil

Boxed Warning 11/2025 Dosage and Administration, Evaluation and Testing for DPD Deficiency Before Initiating Fluorouracil ( 2.1 ) 11/2025 Warnings and Precautions, Serious Adverse Reactions or Death from Dihydropyrimidine Dehydrogenase (DPD) Deficiency ( 5.1 ) 11/2025

1 INDICATIONS AND USAGE 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

1.1 Adenocarcinoma of the Colon and Rectum

1.2 Adenocarcinoma of the Breast

1.3 Gastric Adenocarcinoma

1.4 Pancreatic Adenocarcinoma

2 DOSAGE & ADMINISTRATION •Fluorouracil is recommended for administration either as an intravenous bolus or as an intravenous infusion. (2.1 ) •See Full Prescribing Information for dose individualization (2.1) and dose modifications due to adverse reactions (2.6 ) •See Full Prescribing Information for recommended doses of fluorouracil for adenocarcinoma of the colon and rectum ( 2.2 ) and for recommended doses of fluorouracil as a component of a chemotherapy regimen for adenocarcinoma of the breast (2.3 ), gastric adenocarcinoma ( 2.4 ), pancreatic adenocarcinoma ( 2.5 ) 2.1 General Dose Information Fluorouracil is recommended for administration either as an intravenous bolus or as an intravenous infusion. Do not inject the entire contents of the vial directly into patients. Individualize the dose and dosing schedule of fluorouracil based on tumor type, the specific regimen administered, disease state, response to treatment, and patient risk factors. 2.2 Recommended Dosage for Adenocarcinoma of the Colon and Rectum The recommended dose of fluorouracil, administered in an infusional regimen in combination with leucovorin alone, or in combination with leucovorin and oxaliplatin or irinotecan, is 400 mg/m 2 by intravenous bolus on Day 1, followed by 2400 mg/m 2 to 3000 mg/m 2 intravenously as a continuous infusion over 46 hours every two weeks. The recommended dose of fluorouracil, if administered in a bolus dosing regimen in combination with leucovorin, is 500 mg/m 2 by intravenous bolus on Days 1, 8, 15, 22, 29, and 36 in 8-week cycles. 2.3 Recommended Dosage for Adenocarcinoma of the Breast The recommended dose of fluorouracil, administered as a component of a cyclophosphamide-based multidrug regimen, is 500 mg/m 2 or 600 mg/m 2 intravenously on Days 1 and 8 every 28 days for 6 cycles. 2.4 Recommended Dosage for Gastric Adenocarcinoma The recommended dose of fluorouracil, administered as a component of a platinum-containing multidrug chemotherapy regimen, is 200 mg/m 2 to 1000 mg/m 2 intravenously as a continuous infusion over 24 hours. The frequency of dosing in each cycle and the length of each cycle will depend on the dose of fluorouracil and the specific regimen administered. 2.5 Recommended Dosage for Pancreatic Adenocarcinoma The recommended dose of fluorouracil, administered as an infusional regimen in combination with leucovorin or as a component of a multidrug chemotherapy regimen that includes leucovorin, is 400 mg/m 2 intravenous bolus on Day 1, followed by 2400 mg/m 2 intravenously as a continuous infusion over 46 hours every two weeks. 2.6 Dose Modifications Withhold fluorouracil for any of the following: Development of angina, myocardial infarction/ischemia, arrhythmia, or heart failure in patients with no history of coronary artery disease or myocardial dysfunction [see Warnings and Precautions ( 5.2 )] Hyperammonemic encephalopathy [see Warnings and Precautions ( 5.3 )] Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances [see Warnings and Precautions ( 5.4 )] Grade 3 or 4 diarrhea [see Warnings and Precautions ( 5.5 )] Grade 2 or 3 palmar-plantar erythrodysesthesia (hand-foot syndrome) [see Warnings and Precautions ( 5.6 )] Grade 3 or 4 mucositis [see Warnings and Precautions ( 5.8 )] Grade 4 myelosuppression [see Warnings and Precautions ( 5.7 )] Upon resolution or improvement to Grade 1 diarrhea, mucositis, myelosuppression, or palmar-plantar erythrodysesthesia, resume fluorouracil administration at a reduced dose. There is no recommended dose for resumption of fluorouracil administration following development of any of the following adverse reactions: Cardiac toxicity Hyperammonemic encephalopathy Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances 2.7 Preparation for Administration Fluorouracil is supplied in a single dose vial. The 10 mL/20 mL vial is only intended for preparation in a Pharmacy Admixture Service under appropriate conditions …

3 DOSAGE FORMS AND STRENGTHS Fluorouracil Injection, USP is supplied in a pharmacy bulk package in bottles containing 2.5 grams per 50 mL and 5 grams per 100 mL (50 mg per mL) fluorouracil. Fluorouracil Injection 2.5 grams in a 50 mL bottle and 5 grams in a 100 mL bottle in pharmacy bulk packages ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS SECTION 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 Xiromed, LLC at 844-XIROMED (1-844-947-6633) 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)

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)

7 DRUG 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.

8 USE IN SPECIFIC POPULATIONS •Nursing Mothers: Discontinue drug or discontinue nursing. ( 8.3 ) •Females and Males of Reproductive Potential: Provide pregnancy planning and prevention counseling. ( 5.10 , 8.1 , 8.6 ) 8.1 Pregnancy 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 microanophthalmos. 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. 8.3 Nursing Mothers It is not known whether fluorouracil or its metabolites are present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from fluorouracil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Reported clinical experience has not identified differences in safety or effectiveness between the elderly and younger patients. 8.6 Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, fluorouracil can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with fluorouracil and for up to 3 months following cessation of therapy [see Use in Specific Populations ( 8.1 )] . Males Fluorouracil may damage spermatozoa. Advise males with female partners of reproductive potential to use effective contraception during and for 3 months following cessation of therapy with fluorouracil [see Nonclinical Toxicology ( 13.1 )]. Infertility Females Advise females of reproductive potential that, based on animal data, fertility may be impaired while receiving fluorouracil [see Nonclinical Toxicology ( 13.1) ]. Males Advise males of reproductive potential that, based on animal data, fertility may be impaired while receiving fluorouracil [see Nonclinical Toxicology ( 13.1) ]. 8.6 Females and Males of Reproductive Potential 8.6 Females and Males of Reproductive Potential

12.1 Mechanism of Action Fluorouracil is a nucleoside metabolic inhibitor that interferes with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibits the formation of ribonucleic acid (RNA); these affect rapidly growing cells and may lead to cell death. Fluorouracil is converted to three main active metabolites: 5-fluoro-2′- deoxyuridine-5′-monophosphate (FdUMP), 5-fluorouridine-5′-triphosphate (FUTP) and 5-fluoro-2′-deoxyuridine-5′-triphosphate (FdUTP). These metabolites have several effects including the inhibition of thymidylate synthase by FdUMP, incorporation of FUTP into RNA and incorporation of FdUTP into DNA.

11 DESCRIPTION Fluorouracil injection, USP, a nucleoside metabolic inhibitor, is a colorless to yellow aqueous, sterile, nonpyrogenic injectable solution available in a pharmacy bulk package, a sterile preparation that contains doses for multiple patients for intravenous administration. Each mL contains 50 mg fluorouracil in water for injection, USP. The 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. Its structural formula is: C 4 H 3 FN 2 O 2 M.W. 130.08 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. fluor-struc-01.jpg

10 OVERDOSAGE Administer uridine triacetate within 96 hours following the end of fluorouracil infusion for management of fluorouracil overdose.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Fluorouracil Injection, USP is supplied in a Pharmacy Bulk Package as follows: NDC Fluorouracil Injection, USP (50 mg per mL) Package Factor 25021-215-98 2.5 grams per 50 mL Pharmacy Bulk Bottle 1 bottle per carton 25021-215-99 5 grams per 100 mL Pharmacy Bulk Bottle 1 bottle per carton Fluorouracil Injection, USP, a nucleoside metabolic inhibitor, is a colorless to faint yellow, aqueous, injectable solution available in a pharmacy bulk package, a sterile preparation that contains doses for multiple patients for intravenous administration. 16.2 Storage Storage Conditions Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Do not freeze. Protect from light. Retain in carton until time of use. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex. Fluorouracil is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References ( 15 )] .

16.1 How Supplied Fluorouracil Injection, USP is supplied in a Pharmacy Bulk Package as follows: NDC Fluorouracil Injection, USP (50 mg per mL) Package Factor 25021-215-98 2.5 grams per 50 mL Pharmacy Bulk Bottle 1 bottle per carton 25021-215-99 5 grams per 100 mL Pharmacy Bulk Bottle 1 bottle per carton Fluorouracil Injection, USP, a nucleoside metabolic inhibitor, is a colorless to faint yellow, aqueous, injectable solution available in a pharmacy bulk package, a sterile preparation that contains doses for multiple patients for intravenous administration.