HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Fluorouracil Injection, USP is supplied in Pharmacy Bulk Package as follows:NDCFluorouracil Injection, USP (50 mg per mL)Package Factor25021-215-982.5 grams per 50 mL Pharmacy Bulk Bottle1 bottle per carton25021-215-995 grams per 100 mL Pharmacy Bulk Bottle1 bottle per cartonFluorouracil Injection, USP, nucleoside metabolic inhibitor, is colorless to faint yellow, aqueous, injectable solution available in pharmacy bulk package, sterile preparation that contains doses for multiple patients for intravenous administration.. 16.2 Storage. Storage ConditionsStore at 20 to 25C (68 to 77F). [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 cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Reported clinical experience has not identified differences in safety or effectiveness between the elderly and younger patients.

ADVERSE REACTIONS SECTION.

6 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)] 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 Sagent Pharmaceuticals, Inc. at 1-866-625-1618 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hematologic: pancytopenia [see Warnings and Precautions (5.7)] Gastrointestinal: gastrointestinal ulceration, nausea, vomitingAllergic Reactions: anaphylaxis and generalized allergic reactionsNeurologic: nystagmus, headacheDermatologic: dry skin; fissuring; photosensitivity, as manifested by erythema or increased pigmentation of the skin; vein pigmentationOphthalmic: lacrimal duct stenosis, visual changes, lacrimation, photophobiaPsychiatric: euphoriaMiscellaneous: thrombophlebitis, epistaxis, nail changes (including loss of nails).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been performed with fluorouracil. Fluorouracil was mutagenic in vitro in the bacterial reverse mutation (Ames) assay and induced chromosomal aberrations in hamster fibroblasts in vitro and in mouse bone marrow in the in vivo mouse micronucleus assay.Administration of fluorouracil intraperitoneally to male rats at dose levels equal to or greater than 1.7-fold the human dose of 12 mg/kg induced chromosomal aberrations in spermatogonia and inhibition of spermatogonia differentiation resulting in transient infertility. In female rats, intraperitoneal administration of fluorouracil during the pre-ovulatory phases of oogenesis at dose levels equal to or greater than 0.33 times human dose of 12 mg/kg resulted in decreased incidence of fertile matings, increased pre-implantation loss, and fetotoxicity.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Fluorouracil is nucleoside metabolic inhibitor that interferes with the synthesis of deoxyribonucleic acid (DNA) and to 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-5triphosphate (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. 12.3 Pharmacokinetics. DistributionFollowing bolus intravenous injection, fluorouracil distributes throughout the body including the intestinal mucosa, bone marrow, liver, cerebrospinal fluid and brain tissue.. EliminationFollowing bolus intravenous injection, to 20 of the parent drug is excreted unchanged in the urine in six hours. The remaining percentage of the administered dose is metabolized, primarily in the liver. The metabolites of fluorouracil (e.g., urea and -fluoro-ss-alanine) are excreted in the urine over to hours.Following bolus intravenous injection of fluorouracil, as single agent, the elimination half-life increased with dose from to 20 minutes.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Fluorouracil Injection, USP, nucleoside metabolic inhibitor, is colorless to faint yellow, aqueous, sterile, nonpyrogenic injectable solution available in pharmacy bulk package, 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, fluorinated pyrimidine, is 5-fluoro-2,4 (1H,3H)-pyrimidinedione. Its structural formula is:Molecular formula: C4H3FN2O2 Molecular weight: 130.08 g/mole. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Fluorouracil injection 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 injection for adenocarcinoma of the colon and rectum (2.2) and for recommended doses of fluorouracil injection as component of chemotherapy regimen for adenocarcinoma of the breast (2.3), gastric adenocarcinoma (2.4), pancreatic adenocarcinoma (2.5)Pharmacy Bulk Package: Prepare doses for more than one patient in Pharmacy Admixture Service under appropriate conditions for cytotoxic drugs. Do not inject entire contents of vial directly into patients. Use within hours of puncture (2.7, 2.8). Fluorouracil injection 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 injection for adenocarcinoma of the colon and rectum (2.2) and for recommended doses of fluorouracil injection as component of chemotherapy regimen for adenocarcinoma of the breast (2.3), gastric adenocarcinoma (2.4), pancreatic adenocarcinoma (2.5). Pharmacy Bulk Package: Prepare doses for more than one patient in Pharmacy Admixture Service under appropriate conditions for cytotoxic drugs. Do not inject entire contents of vial directly into patients. Use within hours of puncture (2.7, 2.8). 2.1 General Dosage Information. Fluorouracil injection 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 injection 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 injection, administered in an infusional regimen in combination with leucovorin alone, or in combination with leucovorin and oxaliplatin or irinotecan, is 400 mg/m2 by intravenous bolus on Day 1, followed by 2,400 mg/m2 to 3,000 mg/m2 intravenously as continuous infusion over 46 hours every two weeks.The recommended dose of fluorouracil injection, if administered in bolus dosing regimen in combination with leucovorin, is 500 mg/m2 by intravenous bolus on Days 1, 8, 15, 22, 29, and 36 in 8-week cycles.. The recommended dose of fluorouracil injection, administered in an infusional regimen in combination with leucovorin alone, or in combination with leucovorin and oxaliplatin or irinotecan, is 400 mg/m2 by intravenous bolus on Day 1, followed by 2,400 mg/m2 to 3,000 mg/m2 intravenously as continuous infusion over 46 hours every two weeks.. The recommended dose of fluorouracil injection, if administered in bolus dosing regimen in combination with leucovorin, is 500 mg/m2 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 injection, administered as component of cyclophosphamide-based multidrug regimen, is 500 mg/m2 or 600 mg/m2 intravenously on Days and every 28 days for cycles.. The recommended dose of fluorouracil injection, administered as component of cyclophosphamide-based multidrug regimen, is 500 mg/m2 or 600 mg/m2 intravenously on Days and every 28 days for cycles.. 2.4 Recommended Dosage for Gastric Adenocarcinoma. The recommended dose of fluorouracil injection, administered as component of platinum-containing multidrug chemotherapy regimen, is 200 mg/m2 to 1,000 mg/m2 intravenously as 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 injection and the specific regimen administered.. The recommended dose of fluorouracil injection, administered as component of platinum-containing multidrug chemotherapy regimen, is 200 mg/m2 to 1,000 mg/m2 intravenously as 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 injection and the specific regimen administered.. 2.5 Recommended Dosage for Pancreatic Adenocarcinoma. The recommended dose of fluorouracil injection, administered as an infusional regimen in combination with leucovorin or as component of multidrug chemotherapy regimen that includes leucovorin, is 400 mg/m2 intravenous bolus on Day 1, followed by 2,400 mg/m2 intravenously as continuous infusion over 46 hours every two weeks.. The recommended dose of fluorouracil injection, administered as an infusional regimen in combination with leucovorin or as component of multidrug chemotherapy regimen that includes leucovorin, is 400 mg/m2 intravenous bolus on Day 1, followed by 2,400 mg/m2 intravenously as continuous infusion over 46 hours every two weeks.. 2.6 Dose Modifications. Withhold fluorouracil injection 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 or diarrhea [see Warnings and Precautions (5.5)]Grade or palmar-plantar erythrodysesthesia (hand-foot syndrome) [see Warnings and Precautions (5.6)]Grade or mucositis [see Warnings and Precautions (5.8)]Grade myelosuppression [see Warnings and Precautions (5.7)]Upon resolution or improvement to Grade diarrhea, mucositis, myelosuppression, or palmar-plantar erythrodysesthesia, resume fluorouracil injection administration at reduced dose.There is no recommended dose for resumption of fluorouracil injection administration following development of any of the following adverse reactions:Cardiac toxicityHyperammonemic encephalopathyAcute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances. 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 or diarrhea [see Warnings and Precautions (5.5)]. Grade or palmar-plantar erythrodysesthesia (hand-foot syndrome) [see Warnings and Precautions (5.6)]. Grade or mucositis [see Warnings and Precautions (5.8)]. Grade myelosuppression [see Warnings and Precautions (5.7)]. Cardiac toxicity. Hyperammonemic encephalopathy. Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances. 2.7 Preparation for Administration. Fluorouracil injection is supplied in pharmacy bulk package consisting of vial. The pharmacy bulk package can be used to prepare doses for more than one patient. It is not supplied with sterile transfer device, which is required for dispensing when multiple doses will be prepared from the single vial. The 50 mL vial is only intended for preparation in Pharmacy Admixture Service under appropriate conditions for cytotoxic drugs [see References (15)]. Store vial at room temperature.Using aseptic conditions, penetrate the container closure once with suitable sterile transfer device or dispensing set that allows measured distribution of the contents. Record the date and time the vial was opened on the vial label. Discard the pharmacy bulk package hours after penetration of the container closure.Withdraw the calculated dose for an individual patient into sterile syringe. Inspect the solution in syringe for particulate matter and discoloration prior to administration or further dilution. Discard syringe if the solution is discolored or contains particulate matter.. 2.8 Administration. Do not administer in the same intravenous line concomitantly with other medicinal products.For bolus administration, store undiluted fluorouracil injection in the syringe for up to hours at room temperature (25C). Administer fluorouracil injection as an intravenous bolus through an established intravenous line.Store diluted solutions of fluorouracil injection for up to hours at room temperature (25C) prior to administration to the patient. For intravenous infusion regimens, administer through central venous line using an infusion pump.

DOSAGE FORMS & STRENGTHS SECTION.

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

DRUG INTERACTIONS SECTION.

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.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Fluorouracil Injection is indicated for the treatment of patients with:. Fluorouracil Injection is nucleoside metabolic inhibitor indicated for the treatment of patients withAdenocarcinoma of the Colon and Rectum (1.1)Adenocarcinoma of the Breast (1.2)Gastric Adenocarcinoma (1.3)Pancreatic Adenocarcinoma (1.4). 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise:Patients to notify their healthcare provider if they have known DPD deficiency. Advise patients if they have complete or near complete absence of DPD activity, they are at an increased risk of severe and life-threatening mucositis, diarrhea, neutropenia and neurotoxicity [see Warnings and Precautions (5.1)].Patients of the risk of cardiotoxicity. Advise patients to immediately contact their healthcare provider or to go to an emergency room for new onset of chest pain, shortness of breath, dizziness, or lightheadedness [see Warnings and Precautions (5.2)].Patients to immediately contact their healthcare provider or go to an emergency room for new onset of confusion, disorientation, or otherwise altered mental status; difficulty with balance or coordination; or visual disturbances [see Warnings and Precautions (5.3, 5.4)].Patients to contact their healthcare provider for severe diarrhea or for painful mouth sores with decreased oral intake of food or fluids [see Warnings and Precautions (5.5, 5.8)].Patients to contact their healthcare provider for tingling or burning, redness, flaking, swelling, blisters, or sores on the palms of their hands or soles of their feet [see Warnings and Precautions (5.6)].Patients of the importance of keeping appointments for blood tests. Instruct patients to monitor their temperature on daily basis and to immediately contact their healthcare provider for fever or other signs of infection [see Warnings and Precautions (5.7)].Patients to notify their healthcare provider of all drugs they are taking, including warfarin or other coumarin-derivative anticoagulants. Advise patients of the importance of keeping appointments for blood tests [see Warnings and Precautions (5.9)].Females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with fluorouracil and for up to months after the last dose of fluorouracil. Instruct female patients to contact their healthcare provider if they become pregnant, if pregnancy occurs during fluorouracil treatment or during the months following the last dose [see Warnings and Precautions (5.10), Use in Specific Populations (8.1 and 8.6), and Nonclinical Toxicology (13.1)].Females and males of reproductive potential may have impaired fertility while receiving fluorouracil, based on animal data [see Use in Specific Populations (8.6) and Nonclinical Toxicology (13.1)].Nursing mothers to discontinue nursing [see Use in Specific Populations (8.3)].SAGENT(R) Mfd. for SAGENT PharmaceuticalsSchaumburg, IL 60195 (USA)Made in China(C)2017 Sagent Pharmaceuticals, Inc.Revised: January 2017SAGENT Pharmaceuticals(R) Patients to notify their healthcare provider if they have known DPD deficiency. Advise patients if they have complete or near complete absence of DPD activity, they are at an increased risk of severe and life-threatening mucositis, diarrhea, neutropenia and neurotoxicity [see Warnings and Precautions (5.1)].. Patients of the risk of cardiotoxicity. Advise patients to immediately contact their healthcare provider or to go to an emergency room for new onset of chest pain, shortness of breath, dizziness, or lightheadedness [see Warnings and Precautions (5.2)].. Patients to immediately contact their healthcare provider or go to an emergency room for new onset of confusion, disorientation, or otherwise altered mental status; difficulty with balance or coordination; or visual disturbances [see Warnings and Precautions (5.3, 5.4)].. Patients to contact their healthcare provider for severe diarrhea or for painful mouth sores with decreased oral intake of food or fluids [see Warnings and Precautions (5.5, 5.8)].. Patients to contact their healthcare provider for tingling or burning, redness, flaking, swelling, blisters, or sores on the palms of their hands or soles of their feet [see Warnings and Precautions (5.6)].. Patients of the importance of keeping appointments for blood tests. Instruct patients to monitor their temperature on daily basis and to immediately contact their healthcare provider for fever or other signs of infection [see Warnings and Precautions (5.7)].. Patients to notify their healthcare provider of all drugs they are taking, including warfarin or other coumarin-derivative anticoagulants. Advise patients of the importance of keeping appointments for blood tests [see Warnings and Precautions (5.9)].. Females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with fluorouracil and for up to months after the last dose of fluorouracil. Instruct female patients to contact their healthcare provider if they become pregnant, if pregnancy occurs during fluorouracil treatment or during the months following the last dose [see Warnings and Precautions (5.10), Use in Specific Populations (8.1 and 8.6), and Nonclinical Toxicology (13.1)].. Females and males of reproductive potential may have impaired fertility while receiving fluorouracil, based on animal data [see Use in Specific Populations (8.6) and Nonclinical Toxicology (13.1)].. Nursing mothers to discontinue nursing [see Use in Specific Populations (8.3)].

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Fluorouracil is nucleoside metabolic inhibitor that interferes with the synthesis of deoxyribonucleic acid (DNA) and to 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-5triphosphate (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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been performed with fluorouracil. Fluorouracil was mutagenic in vitro in the bacterial reverse mutation (Ames) assay and induced chromosomal aberrations in hamster fibroblasts in vitro and in mouse bone marrow in the in vivo mouse micronucleus assay.Administration of fluorouracil intraperitoneally to male rats at dose levels equal to or greater than 1.7-fold the human dose of 12 mg/kg induced chromosomal aberrations in spermatogonia and inhibition of spermatogonia differentiation resulting in transient infertility. In female rats, intraperitoneal administration of fluorouracil during the pre-ovulatory phases of oogenesis at dose levels equal to or greater than 0.33 times human dose of 12 mg/kg resulted in decreased incidence of fertile matings, increased pre-implantation loss, and fetotoxicity.

NURSING MOTHERS SECTION.

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, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

OVERDOSAGE SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL Bottle LabelNDC 25021-215-98Rx onlyFluorouracil Injection, USPPHARMACY BULK PACKAGENOT FOR DIRECT INFUSION2.5 grams per 50 mL(50 mg per mL)For Intravenous UseCaution: Cytotoxic Agent. PACKAGE LABEL PRINCIPAL DISPLAY PANEL Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness in pediatric patients have not been established.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. DistributionFollowing bolus intravenous injection, fluorouracil distributes throughout the body including the intestinal mucosa, bone marrow, liver, cerebrospinal fluid and brain tissue.. EliminationFollowing bolus intravenous injection, to 20 of the parent drug is excreted unchanged in the urine in six hours. The remaining percentage of the administered dose is metabolized, primarily in the liver. The metabolites of fluorouracil (e.g., urea and -fluoro-ss-alanine) are excreted in the urine over to hours.Following bolus intravenous injection of fluorouracil, as single agent, the elimination half-life increased with dose from to 20 minutes.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category D. Risk SummaryThere 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 pregnant woman. Administration of fluorouracil to rats and mice during selected periods of organogenesis, at doses lower than 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 fetus [see Clinical Pharmacology (12.1)].. Animal DataMalformations 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 human dose of 12 mg/kg on mg/m2 basis) for 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 human dose of 12 mg/kg on mg/m2 basis) for 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 human dose of 12 mg/kg on mg/m2 basis resulted in abortion; at 50% lower dose, resorptions and decreased fetal body weights were reported.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2)07/2016.

REFERENCES SECTION.

15 REFERENCES. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL UNCLASSIFIED SECTION.

1.1 Adenocarcinoma of the Colon and Rectum.

STORAGE AND HANDLING SECTION.

16.2 Storage. Storage ConditionsStore at 20 to 25C (68 to 77F). [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 cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)].

USE IN SPECIFIC POPULATIONS SECTION.

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). 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 SummaryThere 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 pregnant woman. Administration of fluorouracil to rats and mice during selected periods of organogenesis, at doses lower than 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 fetus [see Clinical Pharmacology (12.1)].. Animal DataMalformations 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 human dose of 12 mg/kg on mg/m2 basis) for 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 human dose of 12 mg/kg on mg/m2 basis) for 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 human dose of 12 mg/kg on mg/m2 basis resulted in abortion; at 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, 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. FemalesBased on its mechanism of action, fluorouracil can cause fetal harm when administered to pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with fluorouracil and for up to months following cessation of therapy [see Use in Specific Populations (8.1)].. MalesFluorouracil may damage spermatozoa. Advise males with female partners of reproductive potential to use effective contraception during and for months following cessation of therapy with fluorouracil [see Nonclinical Toxicology (13.1)]. Infertility. FemalesAdvise females of reproductive potential that, based on animal data, fertility may be impaired while receiving fluorouracil [see Nonclinical Toxicology (13.1)].. MalesAdvise males of reproductive potential that, based on animal data, fertility may be impaired while receiving fluorouracil [see Nonclinical Toxicology (13.1)].

WARNINGS AND PRECAUTIONS SECTION.

5 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 reduced dose. (5.6)Myelosuppression: Fluorouracil can cause severe and fatal myelosuppression. Withhold fluorouracil until severe myelosuppression resolves, then resume at reduced dose. (5.7)Mucositis: Fluorouracil can cause severe mucositis. Discontinue fluorouracil until resolved or decreased to Grade 1, then resume at 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. Advise females and males of reproductive potential of the potential risk to fetus. (5.10, 8.1, 8.6). 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 reduced dose. (5.6). Myelosuppression: Fluorouracil can cause severe and fatal myelosuppression. Withhold fluorouracil until severe myelosuppression resolves, then resume at reduced dose. (5.7). Mucositis: Fluorouracil can cause severe mucositis. Discontinue fluorouracil until resolved or decreased to Grade 1, then resume at 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. Advise females and males of reproductive potential of the potential risk to 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 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 or diarrhea until resolved or decreased in intensity to Grade 1, then resume fluorouracil at 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 tingling sensation, pain, swelling, and erythema with tenderness, and desquamation. HFS occurs more commonly when fluorouracil is administered as continuous infusion than when fluorouracil is administered as bolus injection, and has been reported to occur more frequently in patients with previous exposure to chemotherapy. HFS is generally observed after to weeks of fluorouracil administration but may occur earlier. Institute supportive measures for symptomatic relief of HFS. Withhold fluorouracil administration for Grade or HFS; resume fluorouracil at 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 and 14 days after fluorouracil administration. Obtain complete blood counts prior to each treatment cycle, weekly if administered on weekly or similar schedule, and as needed. Withhold fluorouracil until Grade myelosuppression resolves; resume fluorouracil at reduced dose when myelosuppression has resolved or improved to Grade 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 or mucositis; resume fluorouracil at 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 pregnant woman. In animal studies, administration of fluorouracil at doses lower than 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 fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for months following cessation of therapy with fluorouracil [see Use in Specific Populations (8.1, 8.6), Clinical Pharmacology (12.1), and Nonclinical Toxicology (13.1)].