Fluorouracil

FLUOROURACIL- fluorouracil injection, solution
Xiromed LLC

PRINCIPAL DISPLAY PANEL — 10 mL Container LabelPRINCIPAL DISPLAY PANEL — 10 mL Carton LabelPRINCIPAL DISPLAY PANEL — 20 mL Container LabelPRINCIPAL DISPLAY PANEL — 20 mL Carton Label

1 INDICATIONS & USAGE

Fluorouracil is indicated for the treatment of patients with:
1.1Adenocarcinoma of the Colon and Rectum
1.2Adenocarcinoma of the Breast
1.3Gastric Adenocarcinoma1.4Pancreatic Adenocarcinoma

2 DOSAGE & ADMINISTRATION


2.1General Dose 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.


2.2Recommended 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.


2.3Recommended 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.


2.5Recommended 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.


2.6Dose 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


2.7Preparation for Administration
Fluorouracil is supplied in a in a single dose vial. The 10 mL/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.



2.8Administration
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 & STRENGTHS

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

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS


5.1Increased 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.
5.2Cardiotoxicity
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.



5.3Hyperammonemic 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.
5.4Neurologic 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.
5.5Diarrhea
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.
5.7Myelosuppression
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.
5.8Mucositis
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.
5.9Increased 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)].

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