Fluorouracil

FLUOROURACIL — fluorouracil injection, solution
Gland Pharma Limited

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

2 DOSAGE AND ADMINISTRATION

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 leucovorin alone, or in combination with leucovorin and oxaliplatin or irinotecan, is 400 mg/m2 by intravenous bolus on Day 1, followed by 2400 mg/m2 to 3000 mg/m2 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/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, administered as a component of a cyclophosphamide-based multidrug regimen, is 500 mg/m2 or 600 mg/m2 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/m2 to 1000 mg/m2 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/m2 intravenous bolus on Day 1, followed by 2400 mg/m2 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 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/100 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 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 a pharmacy bulk package as a vial containing 2.5 g/50 mL (50 mg/mL) and 5 g/100 mL (50 mg/mL) fluorouracil.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Serious Adverse Reactions from DihydropyrimidineDehydrogenase (DPD) Deficiency

Patients with certain homozygous or compound heterozygous variants in the DPYD gene known to result in complete or near complete absence of DPD activity (complete DPD deficiency) 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). Patients with partial DPD activity (partial DPD deficiency) may also have increased risk of serious, including fatal, adverse reactions.
Fluorouracil is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency.
Withhold or permanently discontinue fluorouracil based on clinical assessment of the onset, duration, and severity of the observed adverse events in patients with evidence of acute early-onset or unusually severe reactions, which may indicate complete DPD deficiency. No fluorouracil dose has been proven safe for patients with complete DPD deficiency. There are insufficient data to recommend a specific dose in patients with partial DPD deficiency.
Consider testing for genetic variants of DPYD prior to initiating fluorouracil to reduce the risk of serious adverse reactions if the patient’s clinical status permits and based on clinical judgement [see Clinical Pharmacology (12.5)]. Serious adverse reactions may still occur even if no DPYD variants are identified. An FDA-authorized test for the detection of genetic variants of DPYD to identify patients at risk of serious adverse reactions due to increased systemic exposure to fluorouracil is not currently available. Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify).

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