Fluorouracil

FLUOROURACIL — fluorouracil injection, solution
Alembic Pharmaceuticals Inc.

1 INDICATIONS AND USAGE

1.1 Adenocarcinoma of the Colon and Rectum

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1.2 Adenocarcinoma of the Breast

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1.3 Gastric Adenocarcinoma

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1.4 Pancreatic Adenocarcinoma

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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 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, USP is supplied as a pharmacy bulk package as a vial containing 2.5 g/50 mL (50 mg/mL) Fluorouracil.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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.