Fluorouracil

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)] To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 864-879-9994 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)

4 CONTRAINDICATIONS None. None (4)

11 DESCRIPTION Fluorouracil injection, a nucleoside metabolic inhibitor, is a colorless to faint yellow, aqueous, sterile, nonpyrogenic injectable solution available in 10 mL and 20 mL, a sterile preparation that contains single dose vial 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 (1H,3H)-pyrimidinedione. Its structural formula is: Molecular formula: C 4 H 3 FN 2 O 2 Molecular weight : 130.08 fluorouracil-spl-structure

2 DOSAGE AND 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 Dosage 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 leucovor in 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 in a single dose vial. The 10 mL/20 mL vial is only intended for preparation in a 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 a suitable sterile transfer device or dispensing set that allows measured distribution of the contents. Withdraw the calculated dose for an individual patient into a 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 in the syringe for up to 4 hours at room temperature (25°C). Administer fluorouracil as an intravenous bolus through an established intravenous line. Store diluted solutions of fluorouracil for up to 4 hours at room temperature (25°C) prior to administration to the patient. For intravenous infusion regimens, administer through a central venous line using an infusion pump.

1 INDICATIONS AND USAGE Fluorouracil is indicated for the treatment of patients with: 1.1 Adenocarcinoma of the Colon and Rectum 1.2 Adenocarcinoma of the Breast 1.3 Gastric Adenocarcinoma 1.4 Pancreatic Adenocarcinoma 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)

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

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.

12 CLINICAL PHARMACOLOGY 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. 12.3 Pharmacokinetics Distribution Following bolus intravenous injection, fluorouracil distributes throughout the body including the intestinal mucosa, bone marrow, liver, cerebrospinal fluid and brain tissue. Elimination Following bolus intravenous injection, 5 – 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 α-fluoro-ßalanine) are excreted in the urine over 3 to 4 hours. Following bolus intravenous injection of fluorouracil, as a single agent, the elimination half-life increased with dose from 8 to 20 minutes.

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.

12.3 Pharmacokinetics Distribution Following bolus intravenous injection, fluorouracil distributes throughout the body including the intestinal mucosa, bone marrow, liver, cerebrospinal fluid and brain tissue. Elimination Following bolus intravenous injection, 5 – 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 α-fluoro-ßalanine) are excreted in the urine over 3 to 4 hours. Following bolus intravenous injection of fluorouracil, as a single agent, the elimination half-life increased with dose from 8 to 20 minutes.

20220915

5

3 DOSAGE FORMS AND STRENGTHS Fluorouracil injection is supplied as single dose vial containing 500 mg/10 mL (50 mg/mL) and 1 g/20 mL (50 mg/mL) fluorouracil. Injection: 500 mg in a 10 mL vial in Single dose vial (3) 1 g in a 20 mL vial in Single dose vial (3)

Fluorouracil Fluorouracil FLUOROURACIL FLUOROURACIL SODIUM HYDROXIDE WATER Fluorouracil Fluorouracil FLUOROURACIL FLUOROURACIL SODIUM HYDROXIDE WATER

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 a human dose of 12 mg/kg resulted in decreased incidence of fertile matings, increased pre-implantation loss, and fetotoxicity.

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 a human dose of 12 mg/kg resulted in decreased incidence of fertile matings, increased pre-implantation loss, and fetotoxicity.

ANDA210123

Fluorouracil

Fluorouracil

68083-269

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Carton Label - 500 mg/10 mL : NDC 68083-269-10 Rx only Fluorouracil Injection, USP 500 mg/10 mL (50 mg/mL) For Intravenous Use Only CAUTION: CYTOTOXIC AGENT Ten 10 mL Single-Dose Vials Vial Label - 500 mg/10 mL : NDC 68083-269-01 Rx only Fluorouracil Injection, USP 500 mg/10 mL (50 mg/mL) For Intravenous Use Only CAUTION: CYTOTOXIC AGENT 10 mL Single-Dose Vials Carton Label - 1 g/20 mL : NDC 68083-270-10 Rx only Fluorouracil Injection, USP 1 g/20 mL (50 mg/mL) For Intravenous Use Only CAUTION: CYTOTOXIC AGENT Ten 20 mL Single-Dose Vials Vial Label - 1 g/20 mL : NDC 68083-270-01 Rx only Fluorouracil Injection, USP 1 g/20 mL (50 mg/mL) For Intravenous Use Only CAUTION: CYTOTOXIC AGENT 20 mL Single-Dose Vials fluorouracil-spl-carton-10-ml fluorouracil-spl-vial-10-ml fluorouracil-spl-carton-20-ml fluorouracil-spl-vial-20-ml

Dosage and Administration 07/2016

17 PATIENT COUNSELING INFORMATION Advise: • Patients to notify their healthcare provider if they have a 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 a 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 3 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 3 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)]. Manufactured by: Gland Pharma Limited, India. AP/DRUGS/03/2011 May 2017

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

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

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.

8.1 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 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)].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Fluorouracil injection is supplied in single dose vial available in a box containing ten vials, as listed below: • NDC 68083-269-10: one box with ten vials, containing 500 mg/10 mL (50 mg/mL) fluorouracil • NDC 68083-270-10: one box with ten vials, containing 1 g/20 mL (50 mg/mL) fluorouracil 16.2 Storage Store at 20°C to 25°C (68°F to 77°F). Excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Retain in carton until time of use. Fluorouracil is a cytotoxic drug. Follow applicable special handling and disposable procedures [see References (15)].