Fluorouracil (Systemic)

Brand names: Adrucil
Drug class: Antineoplastic Agents

Usage of Fluorouracil (Systemic)

Cancers

Treatment of adenocarcinoma of the colon, rectum, breast, stomach, and pancreas.

Adjunct to surgery for the treatment of various solid tumors (e.g., adenocarcinoma of the colon, rectal carcinoma).

Colorectal Cancer

Drug of choice (combined with leucovorin or levoleucovorin and other drugs [e.g., irinotecan, oxaliplatin]) for advanced colorectal cancer in the adjuvant or metastatic setting.

Doublet regimens (i.e., fluorouracil, oxaliplatin, and leucovorin or levoleucovorin [FOLFOX]; fluorouracil, irinotecan, and leucovorin or levoleucovorin [FOLFIRI]; Capecitabine and oxaliplatin [CapeOx; CapOx]) are the current standard of care for the adjuvant or palliative treatment of advanced colorectal cancer.

Fluorouracil combined with leucovorin or levoleucovorin is an acceptable treatment option in limited-resource settings or in patients unable to tolerate a doublet regimen.

Weekly schedule of fluorouracil/leucovorin (high-dose leucovorin or Roswell Park regimen) has equal efficacy as monthly schedule (low-dose or Mayo Clinic schedule), but the weekly schedule is a preferred regimen for adjuvant therapy because of ease of use and less toxicity. (See Colorectal Cancer under Dosage and Administration.)

Bimonthly, continuous IV infusion schedule of fluorouracil/leucovorin (LV5FU2 or deGramont regimen) also evaluated as adjuvant therapy and shown to be safer than direct IV injection regimen of these drugs. Simplified version of this regimen also evaluated. (See Colorectal Cancer under Dosage and Administration.)

Role of regional adjuvant therapy (e.g., portal vein or hepatic artery infusion† [off-label]) for liver metastases requires further elucidation.

Leucovorin and levoleucovorin enhance cytotoxicity, potentiate fluorouracil antineoplastic activity, and improve response for advanced colorectal carcinoma treatment.

Leucovorin and levoleucovorin may potentiate risk of fluorouracil GI toxicity (e.g., diarrhea, nausea, stomatitis, vomiting) and myelosuppression.

Breast Cancer

Combined with other drugs (e.g., cyclophosphamide, doxorubicin, methotrexate) as an adjunct to surgery and for metastatic breast cancer.

Decision regarding use of adjuvant endocrine therapy with or without sequential combination chemotherapy may be guided by prognostic tools, such as recurrence score based on 21-gene assay results, to predict absolute benefit of combination chemotherapy in addition to adjuvant endocrine therapy.

Adjunct to surgery, may improve outcome.

Esophageal Cancer

Has been used alone and in combination therapy (e.g., with cisplatin) for the treatment of localized or advanced esophageal cancer† [off-label].

Head and Neck Cancer

Has been used in combination chemotherapy for metastatic or recurrent squamous cell carcinoma of the head and neck† [off-label].

Has been used in combination chemotherapy with radiation therapy for palliative treatment of unresectable locally advanced head and neck cancer, and for larynx preservation in locally advanced laryngeal or hypopharyngeal cancer.

Used in combination with docetaxel and cisplatin as induction therapy prior to radiotherapy or chemoradiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck.

Cervical Cancer

Has been used in combination with cisplatin concurrently with radiation therapy for invasive cervical cancer† [off-label].

Metastatic or recurrent cervical cancer† [off-label].

Renal Cell Carcinoma

Has been used alone or in combination regimens for the treatment of metastatic renal cell carcinoma†.

Carcinoid Tumors

Has been used for the treatment of carcinoid tumors†.

Other Uses

Has been used as second-line therapy in the treatment of ovarian epithelial cancer†, including platinum-refractory disease. Also, cancers of the liver† (e.g., hepatoblastoma†).

Relate drugs

How to use Fluorouracil (Systemic)

Administration

Administer IV.

Has been administered by regional infusion into the venous or arterial blood supply of a tumor† (e.g., portal vein or hepatic artery infusions for liver metastases).

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

2.5- or 5-g pharmacy bulk package is intended for individual dose preparation, not for direct IV infusion.

Use an established IV line to administer fluorouracil by direct IV injection.

For IV infusion regimens, administer fluorouracil via a central venous catheter using a controlled infusion device (e.g., pump).

Avoid extravasation.

Dilution

No dilution necessary for usual injection formulation.

Rate of Administration

Administer by direct IV injection or continuous IV infusion.

Dosage

Base dosage on actual weight.

May calculate dosage based on body surface area.

Individualize dosage and dosage schedule based on tumor type, specific regimen, clinical response, and concomitant comorbidities.

Consult published protocols for the dosage and method and sequence of administration of fluorouracil with other chemotherapeutic agents.

Adults

Colorectal Cancer

Various fluorouracil/leucovorin combination dosage regimens have been used.

IV

Direct IV injection: 500 mg/m2 by direct IV injection in combination with leucovorin or levoleucovorin on days 1, 8, 15, 22, 29, and 36 in each 8-week cycle.

IV infusion: 400 mg/m2 by direct IV injection on day 1 followed by 2400–3000 mg/m2 as a continuous IV infusion over 46 hours every 14 days in combination with leucovorin or levoleucovorin with or without oxaliplatin or irinotecan.

Combination Regimen: Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX) IV

Day 1: Oxaliplatin 85 mg/m2 and leucovorin 200 mg/m2 concurrently (in separate containers using a Y-type administration set) by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 by direct IV injection, and then fluorouracil 600 mg/m2 by IV infusion over 22 hours.

Day 2: Leucovorin 200 mg/m2 by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 by direct IV injection, and then fluorouracil 600 mg/m2 by IV infusion over 22 hours.

Following schedule also used: Oxaliplatin 85–100 mg/m2 and leucovorin 400 mg/m2 by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 by direct IV injection, and then fluorouracil 2400–3000 mg/m2 by IV infusion over 46 hours.

Repeat cycles every 2 weeks.

Combination Regimen: Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) IV

Irinotecan 180 mg/m2 and leucovorin 400 mg/m2 administered concurrently by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 by direct IV injection, and then fluorouracil 2400–3000 mg/m2 by IV infusion over 46 hours; repeat cycles every 2 weeks.

Combination Regimen: Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan (FOLFOXIRI) IV

Irinotecan 165 mg/m2 by IV infusion over 1 hour, followed by leucovorin 200 mg/m2 and oxaliplatin 85 mg/m2 administered concurrently by IV infusion over 2 hours, and then fluorouracil 3200 mg/m2 by IV infusion over 48 hours; repeat cycles every 2 weeks.

Monthly Schedule (Mayo Clinic Regimen) Direct IV Injection

Leucovorin 20 mg/m2 IV or levoleucovorin 10 mg/m2 IV followed by fluorouracil 425 mg/m2 IV; administer fluorouracil and either leucovorin or levoleucovorin daily for 5 consecutive days and repeat regimen at 4-week intervals for 2 additional courses; thereafter, may repeat the regimen at intervals of 4–5 weeks provided toxicity from the previous course has resolved completely. Frequently administered for a total of 6 cycles in the adjuvant setting.

Alternatively, leucovorin 200 mg/m2 IV or levoleucovorin 100 mg/m2 IV over ≥3 minutes followed by fluorouracil 370 mg/m2 IV; administer fluorouracil and either leucovorin or levoleucovorin daily for 5 consecutive days and repeat regimen at 4-week intervals for 2 additional courses; thereafter, may repeat the regimen at intervals of 4–5 weeks provided toxicity from the previous course has resolved completely.

Adjust fluorouracil dosage in subsequent courses according to tolerance; reduce daily fluorouracil dosage by 20% for moderate hematologic or GI toxicity in prior course and by 30% for severe toxicity (leucovorin or levoleucovorin dosage is not adjusted ).

May increase fluorouracil dosage by 10% if no toxicity occurred in the prior course.

Weekly Schedule (Roswell Park Regimen) IV Infusion

Leucovorin 500 mg/m2 as a 2-hour IV infusion followed by fluorouracil 500 mg/m2 as a slow IV injection administered 1 hour after the start of the leucovorin infusion. Administer both drugs weekly for 6 consecutive weeks followed by a 2-week rest; repeat cycles every 8 weeks for a total of 4 courses in the adjuvant setting.

Adjust fluorouracil dosage in subsequent courses according to tolerance; reduce daily fluorouracil dosage by 20% for moderate hematologic or GI toxicity in prior course and by 30% for severe toxicity (leucovorin dosage is not adjusted ).

May increase fluorouracil dosage by 10% if no toxicity occurred in the prior course.

Bimonthly Schedule (Modified deGramont Regimen) IV Infusion

Leucovorin 400 mg/m2 as a 2-hour IV infusion on day 1 followed by fluorouracil 400 mg/m2 as an IV injection on day 1; then fluorouracil 1500 mg/m2 as a continuous IV infusion over 23 hours on days 1 and 2 (i.e., total 3000 mg/m2 by continuous IV infusion over 46 hours); repeat cycles every 2 weeks.

Breast Cancer

Various combination regimens have been used; consult published protocols for dosages and method and sequence of administration.

Avoid arbitrary dose reductions of adjuvant combination chemotherapy; dose intensity appears to be an important factor influencing clinical outcome in early node-positive breast cancer (increasing response with increasing intensity).

IV

500 or 600 mg/m2 IV on days 1 and 8 of each 28-day cycle for a total of 6 cycles in combination with a cyclophosphamide-based regimen.

Combination Regimen: Cyclophosphamide, Methotrexate, and Fluorouracil IV

Regimen containing IV fluorouracil in combination with oral cyclophosphamide and IV methotrexate is described in the table.

Drug

Dose

Administration Days per Cycle

Fluorouracil

600 mg/m2 IV (≤60 yrs of age)

Days 1 and 8

Cyclophosphamide

100 mg/m2 orally

Days 1 through 14

Methotrexate

40 mg/m2 IV (≤60 yrs of age)

Days 1 and 8

Repeat monthly (i.e., allow a 2-week rest period between cycles).

Total of 6–12 cycles (i.e., 6–12 months of therapy); clinical superiority between 6- versus 12-month regimens not demonstrated.

Initial fluorouracil and methotrexate dosages have been reduced in patients >60 years of age. (See Geriatric Patients under Special Populations.)

Also, dosage was reduced if myelosuppression developed.

Sequential Regimen: Cyclophosphamide, Methotrexate, and Fluorouracil Plus Doxorubicin

In early breast cancer and >3 positive axillary lymph nodes, doxorubicin addition may improve outcome, and sequential regimens (i.e., several courses of doxorubicin first) may be more effective than alternating regimens; no additional benefit when fewer positive nodes are present.

IV

Initially, doxorubicin hydrochloride 75 mg/m2 IV at 3-week intervals for 4 doses.

Subsequently, fluorouracil 600 mg/m2 IV, methotrexate 40 mg/m2 IV, and cyclophosphamide 600 mg/m2 IV at 3-week intervals for 8 cycles.

Total of about 9 months of therapy.

Generally, myelosuppression has delayed cycle rather than reducing dosage.

Gastric Cancer IV

200–1000 mg/m2 as a continuous IV infusion over 24 hours in combination with a platinum-based regimen. Consult published protocols for frequency of dosing and duration of each cycle for the specific regimen.

Pancreatic Cancer IV

400 mg/m2 by direct IV injection on day 1 followed by 2400 mg/m2 as a continuous IV infusion over 46 hours every 14 days in combination with leucovorin or as part of a multi-drug regimen containing leucovorin.

Dosage Modification for Toxicity

For grade 3 or 4 diarrhea or mucositis, grade 4 myelosuppression, or grade 2 or 3 palmar-plantar erythrodysesthesia (hand-foot syndrome), withhold therapy; resume therapy at a reduced dosage when the toxicity has resolved or improved to grade 1.

Temporarily withhold therapy if cardiotoxicity (i.e., angina, myocardial infarction or ischemia, arrhythmia, heart failure) develops in patients with no history of coronary artery disease or cardiac dysfunction; also withhold therapy if hyperammonemic encephalopathy or neurologic effects (i.e., acute cerebellar syndrome, confusion, disorientation, ataxia, visual disturbance) occur. Manufacturer makes no dosage recommendations for resumption of fluorouracil therapy following development of cardiotoxicity, hyperammonemic encephalopathy, or neurologic effects.

Special Populations

Geriatric Patients

Breast Cancer

In patients >60 years of age receiving oral cyclophosphamide, IV methotrexate, and IV fluorouracil combination therapy, reduce initial methotrexate dosage to 30 mg/m2 and fluorouracil dosage to 400 mg/m2.

Warnings

Contraindications

  • Manufacturer states none known.

    • Warnings/Precautions

    Dipyrimidine Dehydrogenase (DPD) Activity Deficiency

    Acute early-onset or unusually severe toxicity may indicate near-complete or total absence of DPD activity; withhold or permanently discontinue fluorouracil in such patients.

    Certain homozygous or compound heterozygous mutations in the DPD gene result in complete or near-complete absence of DPD activity. Patients with such mutations are at increased risk for acute early-onset and severe, life-threatening, or fatal toxicity (e.g., mucositis, diarrhea, neutropenia, neurotoxicity). Patients with partial DPD activity also may have increased risk of severe, life-threatening, or fatal toxicity.

    Safety not established in patients with complete absence of DPD activity.

    Data insufficient to support dosage recommendations for those with partial DPD activity.

    Cardiac Effects

    Myocardial ischemia/infarction, heart failure, arrhythmias, and angina (including Prinzmetal variant angina) reported.

    Administration of drug by continuous IV infusion and presence of coronary artery disease may increase risk of cardiotoxicity.

    Safety of resuming fluorouracil after resolution of cardiotoxicity not established.

    Nervous System Effects

    Disorientation, confusion, ataxia, visual disturbances, and acute cerebellar syndrome reported. Insufficient data on risks of resuming fluorouracil after resolution of neurologic adverse effects.

    Hyperammonemic encephalopathy, in the absence of liver disease or other identifiable cause, reported. Altered mental status, confusion, disorientation, ataxia, or coma in presence of elevated serum ammonia concentrations, may occur ≤72 hours following initiation of fluorouracil infusion.

    If hyperammonemic encephalopathy or neurologic effects occur, temporarily interrupt therapy.

    GI Toxicity

    Mucositis, stomatitis, and esophagopharyngitis and subsequent mucosal sloughing or ulceration reported more frequently following administration of the drug by direct IV injection compared with administration by continuous IV infusion. Diarrhea occurs frequently and may be severe.

    Temporarily withhold fluorouracil if grade 3 or 4 diarrhea or mucositis occurs; resume drug at a reduced dosage when the toxicity resolves or improves to grade 1. Potential for diarrhea to result in rapid clinical deterioration and death in patients receiving reduced folates (leucovorin, levoleucovorin) concomitantly; close monitoring is required.

    Initiate fluid and electrolyte replacement or antidiarrheal therapy as clinically necessary.

    Hand-foot Syndrome

    Palmar-plantar erythrodysesthesia (hand-foot syndrome) reported.

    Erythematous, desquamative rash that involves the hands and feet, may be accompanied by tingling sensation, pain, swelling, and erythema with tenderness.

    If grade 2 or 3 hand-foot syndrome occurs, temporarily interrupt therapy until the toxicity resolves or improves to grade 1.

    May be treated with oral pyridoxine therapy or topical emollients (e.g., hand creams, udder balm).

    Hematologic Toxicity

    Myelosuppression (e.g., neutropenia, thrombocytopenia, anemia), sometimes severe or fatal, reported. Nadir neutrophil count usually occurs 9–14 days following initiation of therapy.

    Obtain complete blood cell counts (CBCs) prior to each treatment cycle, weekly (if administered on a weekly or similar schedule), and as clinically indicated.

    If grade 4 myelosuppression occurs, temporarily interrupt therapy until the toxicity resolves or improves to grade 1.

    Fetal/Neonatal Morbidity and Mortality

    May cause fetal harm.

    Advise women of childbearing potential and men with such female partners to use effective contraceptive methods during fluorouracil therapy and for up to 3 months after the last dose of the drug.

    If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

    Impairment of Fertility

    Results of animal studies suggest that fluorouracil may impair male and female fertility.

    Specific Populations

    Pregnancy

    Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

    Lactation

    Not known whether fluorouracil or its metabolites are distributed into human milk. Discontinue nursing or the drug.

    Pediatric Use

    Safety and efficacy in children not established.

    Common Adverse Effects

    Stomatitis, esophagopharyngitis, anorexia, nausea, vomiting, diarrhea, leukopenia (principally granulocytopenia), thrombocytopenia, anemia, alopecia, dermatitis (principally pruritic maculopapular rash).

    What other drugs will affect Fluorouracil (Systemic)

    Drugs Metabolized by Hepatic Microsomal Enzymes

    Substrates of CYP2C9: Fluorouracil or its metabolites may inhibit CYP isoenzyme 2C9.

    Specific Drugs

    Drug

    Interaction

    Comments

    Coumarin anticoagulants (e.g., warfarin)

    Clinically significant elevations in coagulation parameters (e.g., increased prothrombin time [PT], increased INR)

    Closely monitor INR or PT; adjust anticoagulant dosage as necessary

    Leucovorin

    Leucovorin potentiates cytotoxicity of fluorouracil in certain GI cancers

    Leucovorin enhances fluorouracil toxicity

    Used to therapeutic advantage in GI cancers

    Use concomitantly with extreme caution in geriatric or debilitated patients; more likely to develop serious toxicity

    Levoleucovorin

    Levoleucovorin enhances therapeutic effects of fluorouracil in colorectal cancer

    Levoleucovorin enhances fluorouracil toxicity

    Used to therapeutic advantage in colorectal cancer

    Use concomitantly with extreme caution in geriatric or debilitated patients; more likely to develop serious toxicity

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