NDC 50742-423 Fluorouracil

Fluorouracil

NDC Product Code 50742-423

NDC 50742-423-10

Package Description: 1 VIAL in 1 CARTON > 10 mL in 1 VIAL

NDC Product Information

Fluorouracil with NDC 50742-423 is a a human prescription drug product labeled by Ingenus Pharmaceuticals, Llc. The generic name of Fluorouracil is fluorouracil. The product's dosage form is injection, solution and is administered via intravenous form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 1791701 and 1791736.

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Fluorouracil Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SODIUM HYDROXIDE (UNII: 55X04QC32I)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Nucleic Acid Synthesis Inhibitors - [MoA] (Mechanism of Action)
  • Nucleoside Metabolic Inhibitor - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Ingenus Pharmaceuticals, Llc
Labeler Code: 50742
FDA Application Number: ANDA209219 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 12-21-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

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Information for Patients

Fluorouracil Injection

Fluorouracil Injection is pronounced as (floor'' oh ure' a sil)

Why is fluorouracil injection medication prescribed?
Fluorouracil is generally used in combination with other medications to treat colon cancer or rectal cancer (cancer that begins in the large intestine) that has gotten wo...
[Read More]

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Fluorouracil Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

Fluorouracil is a nucleoside metabolic inhibitor indicated for the treatment of patients with

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.

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  • The recommended dose of fluorouracil, administered as a component of a cyclophosphamide-based multidrug regimen, is 500 mg/m2or 600 mg/m2intravenously on Days 1 and 8 every 28 days for 6 cycles.
  • The recommended dose of fluorouracil, administered as a component of a platinum-containing multidrug chemotherapy regimen, is 200 mg/m2to 1000 mg/m2intravenously 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.
  • 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/m2intravenous bolus on Day 1, followed by 2400 mg/m2intravenously 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 toxicityHyperammonemic encephalopathyAcute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances

2.7 Preparation For Administration

Fluorouracil is supplied in a single dose vial. The 10 mL and 20 mL vial are only intended for preparation under appropriate conditions for cytotoxic drugs [see References (15)]. Store vial at room temperatureWithdraw 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. Discard unused portion.

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.

3 Dosage Forms And Strengths

  • Fluorouracil injection is supplied as: Single dose vial containing 500 mg/10 mL (50 mg/mL) fluorouracil.Single dose vial containing 1 g/20 mL (50 mg/mL) fluorouracil.

4 Contraindications

None

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 with fluorouracil [see Use in Specific Populations (8.1, 8.6), Clinical Pharmacology (12.1), and Nonclinical Toxicology (13.1)]

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)]

6.1 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, 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)

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.

8.1 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 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 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 a human dose of 12 mg/kg on a mg/m2 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/m2 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/m2basis 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

ContraceptionFemalesBased 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)].MalesFluorouracil 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)].InfertilityFemalesAdvise 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)].

10 Overdosage

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

11 Description

Fluorouracil injection, USP a nucleoside metabolic inhibitor, is a colorless to yellow, aqueous, sterile, nonpyrogenic injectable solution available in 10 mL and 20 mL, a sterile preparation that contains single dose for intravenous administration. Each mL contains 50 mg fluorouracil, USP 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:

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

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, 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-ß  alanine) 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.

13.3 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.

15 References

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

16.1 Supplied

  • Fluorouracil injection, USP is supplied in single dose vials, available in a box containing one vial, as listed below:NDC 50742-423-10: one box with one vial, containing 500 mg/10 mL (50 mg/mL) fluorouracil.NDC 50742-481-20: one box with one vial, containing 1 g/20 mL (50 mg/mL) fluorouracil.

16.2 Storage

Store at 20°C to 25°C (68°F to 77°F). [see USP Controlled Room Temperature]. DO NOT FREEZE. 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)].

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 for:Ingenus Pharmaceuticals, LLCOrlando, FL 32839-6408Made in SwitzerlandRevised: 04/2019

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