Fluorouracil

Dosage and Administration, Evaluation and Testing for DPD Deficiency Before Initiating Fluorouracil (

Warnings and Precautions, Serious Adverse Reactions or Death from Dihydropyrimidine Dehydrogenase (DPD) Deficiency (

Fluorouracil injection is indicated for the treatment of patients with:

• Fluorouracil injection is recommended for administration either as an intravenous bolus or as an intravenous infusion. (
  2.2 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 based on tumor type, the specific regimen administered, disease state, response to treatment, and patient risk factors.
  )
• See Full Prescribing Information for dose individualization (
  2.2 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 based on tumor type, the specific regimen administered, disease state, response to treatment, and patient risk factors.
  ) and dose modifications due to adverse reactions (
  2.7 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 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 injection administration at a reduced dose.

  
  
  

  There is no recommended dose for resumption of fluorouracil injection administration following development of any of the following adverse reactions:

  • Cardiac toxicity
  • Hyperammonemic encephalopathy
  • Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances
  )
• See Full Prescribing Information for recommended doses of fluorouracil injection for adenocarcinoma of the colon and rectum (
  2.3 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/m²by intravenous bolus on Day 1, followed by 2400 mg/m²to 3000 mg/m²intravenously as a continuous infusion over 46 hours every two weeks.
  • The recommended dose of fluorouracil injection, if administered in a bolus dosing regimen in combination with leucovorin, is 500 mg/m²by intravenous bolus on Days 1, 8, 15, 22, 29, and 36 in 8 week cycles.
  ) and for recommended doses of fluorouracil injection as a component of a chemotherapy regimen for adenocarcinoma of the breast (
  2.4 Recommended Dosage for Adenocarcinoma of the Breast

  • The recommended dose of fluorouracil injection, 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.
  ), gastric adenocarcinoma (
  2.5 Recommended Dosage for Gastric Adenocarcinoma

  • The recommended dose of fluorouracil injection, 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 injection and the specific regimen administered.
  ), pancreatic adenocarcinoma (
  2.6 Recommended Dosage for Pancreatic Adenocarcinoma

  • The recommended dose of fluorouracil injection, 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.
  )
• Single-Dose Vials: Use within 4 hours of puncture (
  2.8 Preparation for Administration

  The 500 mg/10 mL and 1 g/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

  .
  ,
  2.9 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.
  )

Fluorouracil Injection, USP is supplied as a single-dose vial containing 500 mg/10 mL or 1 g/20 mL (50 mg/mL) fluorouracil.

• Nursing Mothers: Discontinue drug or discontinue nursing. (
  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.
  )
• Females and Males of Reproductive Potential: Provide pregnancy planning and prevention counseling. (
  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)]

  .
  ,
  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/m²basis) 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/m²basis) 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/m²basis resulted in abortion; at a 50% lower dose, resorptions and decreased fetal body weights were reported.
  ,
  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)]

  .
  )