Fluorouracil - Fluorouracil injection, Solution

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. (
  2.1 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.
  )
• See Full Prescribing Information for dose individualization (
  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.
  ) and dose modifications due to adverse reactions (
  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 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 (
  2.2 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/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 (
  2.3 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 (
  2.4 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 (
  2.5 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.
  )
• Pharmacy Bulk Package: Prepare doses for more than one patient in a Pharmacy Admixture Service under appropriate conditions for cytotoxic drugs. Do not inject entire contents of vial directly into patients. Use within 4 hours of puncture (
  2.7 Preparation for Administration

  Fluorouracil injection is supplied in a pharmacy bulk package consisting of a vial. The pharmacy bulk package can be used to prepare doses for more than one patient. It is not supplied with a 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 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. Record the date and time the vial was opened on the vial label. Discard the pharmacy bulk package 4 hours after penetration of the container closure.

  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 injection in the syringe for up to 4 hours at room temperature (25°C). Administer fluorouracil injection as an intravenous bolus through an established intravenous line.

  Store diluted solutions of fluorouracil injection 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 pharmacy bulk package as a vial containing 2.5 grams per 50 mL (50 mg per 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 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.
  ,
  8.6 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)]

  .
  )

• Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase (DPD) Deficiency
  : Patients with certain homozygous or compound heterozygous variants in the
  DPYD
  gene are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to fluorouracil (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Fluorouracil is not recommended for use in patients known to have certain homozygous or compound heterozygous
  DPYD
  variants that result in complete absence of DPD activity. Withhold or permanently discontinue based on clinical assessment. No fluorouracil dose has been proven safe in patients with complete absence of DPD activity.
• Cardiotoxicity: Fluorouracil can cause cardiotoxicity, including angina, myocardial infarction/ischemia, arrhythmia, and heart failure. Withhold fluorouracil for cardiac toxicity. (
  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.
  )
• 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 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.
  )
• Neurologic Toxicity: Fluorouracil can cause acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances. Withhold fluorouracil for neurologic toxicity. (
  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.
  )
• Diarrhea: Fluorouracil can cause severe diarrhea. Withhold fluorouracil for severe diarrhea until 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.
  )
• 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 a reduced dose. (
  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 to 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.
  )
• Myelosuppression: Fluorouracil can cause severe and fatal myelosuppression. Withhold fluorouracil until severe myelosuppression resolves, then resume at a reduced dose. (
  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.
  )
• Mucositis: Fluorouracil can cause severe mucositis. Discontinue fluorouracil until resolved or decreased to Grade 1, then resume at a reduced dose. (
  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.
  )
• 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 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)]

  .
  )
• Embryofetal Toxicity: Fluorouracil can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus. (
  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 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.
  ,
  8.6 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)]

  .
  )