Fluorouracil (Systemic)

• If you have an allergy to fluorouracil or any other part of fluorouracil (systemic).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: An infection, low blood cell counts, or poor diet.
• If you are breast-feeding. Do not breast-feed while you take this medicine.

This is not a list of all drugs or health problems that interact with fluorouracil.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use fluorouracil as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.
• It may be given as a shot into a vein.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

• Antineoplastic Agent, Antimetabolite
• Antineoplastic Agent, Antimetabolite (Pyrimidine Analog)

Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. The following adjustments have been suggested:

Bilirubin >5 mg/dL: Avoid use (Floyd 2006).

Hepatic impairment (degree not specified): Administer <50% of dose, then increase if toxicity does not occur (Koren 1992).

Withhold treatment for the following (may resume at a reduced dose following resolution or improvement to grade 1):

Dermatologic toxicity: Grade 2 or 3 palmar-plantar erythrodysesthesia (hand-foot syndrome)

Gastrointestinal toxicity: Grade 3 or 4 diarrhea; grade 3 or 4 mucositis

Hematologic toxicity: Grade 4 myelosuppression

Withhold treatment for the following (there is no recommended dose for resumption):

Cardiovascular toxicity: Angina, MI/ischemia, arrhythmia, or heart failure in patients without a history of coronary artery disease or myocardial dysfunction

CNS toxicity: Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances

Hyperammonemic encephalopathy

Concerns related to adverse effects:

• Bone marrow suppression: Fluorouracil can cause severe and fatal hematologic toxicity (neutropenia, thrombocytopenia, and anemia). The neutrophil nadir usually occurs between 9 to 14 days after administration. Monitor blood counts prior to each treatment cycle, weekly if administered on a weekly or similar schedule, and as clinically indicated. Withhold fluorouracil for grade 4 hematologic toxicity; when blood counts resolve to grade 1 or lower, resume at a reduced dose.

• Cardiotoxicity: Based on postmarketing reports, fluorouracil may cause cardiotoxicity (angina, MI/ischemia, arrhythmia, and heart failure). Risk factors for cardiotoxicity include continuous infusion administration (versus IV bolus) and coronary artery disease. Withhold fluorouracil for cardiotoxicity. The risks of resuming fluorouracil in patients with resolved cardiotoxicity have not been established. In a scientific statement from the AHA, fluorouracil has been determined to be an agent that may either cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate/major) (AHA [Page 2016]).

• GI toxicity: Fluorouracil is associated with severe diarrhea. Withhold treatment for grade 3 or 4 diarrhea until resolved or to grade 1 or lower, then resume fluorouracil at a reduced dose. Administer fluids, electrolyte replacement, and/or antidiarrheal treatments as necessary. Mucositis, stomatitis, or esophagopharyngitis (which may lead to mucosal sloughing or ulceration) may occur with fluorouracil. The incidence of mucositis is reported to be higher with IV bolus fluorouracil administration (vs continuous infusion). Withhold fluorouracil grade 3 or 4 mucositis; resume at a reduced dose once mucositis has resolved to grade 1 or lower.

• Hand-foot syndrome: Fluorouracil is associated with palmar-plantar erythrodysesthesia (hand-foot syndrome; HFS). Symptoms of HFS include a tingling sensation, pain, swelling, erythema with tenderness, and desquamation. HFS occurs more commonly when fluorouracil is administered as a continuous infusion (compared to IV bolus) and has been reported to occur more frequently in patients with prior chemotherapy exposure. The onset of HFS is usually after 8 to 9 weeks of fluorouracil, although may occur earlier. Initiate supportive care for symptomatic relief of HFS. Withhold fluorouracil for grade 2 or 3 HFS; resume at a reduced dose when HFS has resolved to grade 1 or lower.

• Hyperammonemic encephalopathy: Fluorouracil may result in hyperammonemic encephalopathy in the absence of liver disease or other identifiable cause (postmarketing reports). The onset of hyperammonemic encephalopathy signs/symptoms (altered mental status, confusion, disorientation, coma, or ataxia, in the presence of concomitant elevated serum ammonia level) was within 72 hours after fluorouracil infusion initiation. Withhold fluorouracil for hyperammonemic encephalopathy and initiate ammonia-lowering therapy. The risks of resuming fluorouracil in patients with resolved hyperammonemic encephalopathy have not been established.

• Neurotoxicity: Fluorouracil may cause neurologic toxicity, including acute cerebellar syndrome and other neurologic events (postmarketing reports). Neurologic symptoms included confusion, disorientation, ataxia, or visual disturbances. Withhold fluorouracil for neurologic toxicity. There are insufficient data on the risks of resuming fluorouracil in patients with resolved neurologic toxicity.

Disease-related concerns:

• Dihydropyrimidine dehydrogenase deficiency: Patients with select homozygous or compound heterozygous dihydropyrimidine dehydrogenase (DPD) gene mutations 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 (eg, mucositis, diarrhea, neutropenia, neurotoxicity) due to fluorouracil. Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions when administered fluorouracil. Based on clinical assessment of toxicity onset, duration, and severity, withhold or permanently discontinue fluorouracil in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. There is no fluorouracil dose that has been proven safe in patients with complete absence of DPD activity and data are insufficient to recommend a specific dose in patients with partial DPD activity as measured by any specific test.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Warfarin: Clinically significant coagulation parameter elevations have been reported with concomitant use of warfarin and fluorouracil. Closely monitor INR and prothrombin time in patients receiving concomitant coumarin-derivative anticoagulants such as warfarin and adjust the anticoagulant dose accordingly.

Other warnings/precautions:

• Administration safety issues: Serious errors have occurred when doses administered by continuous ambulatory infusion pumps have inadvertently been given over 1 to 4 hours instead of the intended extended continuous infusion duration. Depending on protocol, infusion duration may range from 46 hours to 7 days for fluorouracil continuous infusions. Ambulatory pumps utilized for continuous infusions should have safeguards to allow for detection of programming errors. If using an elastomeric device for ambulatory continuous infusion, carefully select the device and double check the flow rate. Appropriate prescribing (in single daily doses [not course doses] with instructions to infuse over a specific time period), appropriate training/certification/education of staff involved with dispensing and administration processes, and independent double checks should be utilized throughout dispensing and administration procedures (ISMP [Smetzer 2015]).

• Antidote: Uridine triacetate (formerly called vistonuridine), has been studied in cases of fluorouracil overdose. In a clinical study of 98 patients who received uridine triacetate for fluorouracil toxicity (due to overdose, accidental capecitabine ingestion, or possible DPD deficiency), 96 patients recovered fully (Bamat 2013). Of 17 patients receiving uridine triacetate beginning within 8 to 96 hours after fluorouracil overdose, all patients fully recovered (von Borstel 2009). Refer to Uridine Triacetate monograph.

CBC with differential and platelet count (prior to each treatment cycle, weekly if administered on a weekly or similar schedule, and as clinically indicated), renal function tests, LFTs, INR, and prothrombin time (in patients receiving concomitant coumarin-derivative anticoagulants); signs/symptoms of palmar-plantar erythrodysesthesia syndrome, cardiotoxicity, CNS toxicity, stomatitis, diarrhea, and hyperammonemic encephalopathy.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, dry skin, hair loss, or nail changes. Have patient report immediately to prescriber signs of infection; signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding); angina; shortness of breath; excessive weight gain; swelling in the arms or legs; abnormal heartbeat; dizziness; passing out; severe abdominal pain; severe nausea; vomiting; severe diarrhea; swelling of hands or feet; change in balance; severe fatigue; confusion; severe mouth irritation; burning or numbness feeling; involuntary eye movements; headache; mouth sores; sensitivity to lights; severe loss of strength and energy; vision changes; severe injection site pain, burning, edema, or redness; or redness or irritation of palms or soles of feet (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.