Fluorouracil, a pyrimidine antagonist, is an antimetabolite antineoplastic agent.205
Fluorouracil is used for the treatment of adenocarcinoma of the colon, rectum, breast, stomach, and pancreas.205 Fluorouracil is used off-label for a variety of other oncologic indications; refer to current treatment guidelines for the most up-to-date recommendations for use in such indications.
Fluorouracil is used for the treatment of patients with adenocarcinoma of the colon and rectum.205
Prior to the year 2000, fluorouracil was the only useful chemotherapy option available for adjuvant treatment of advanced (stage III) colon cancer.12003 Studies evaluating its efficacy as monotherapy at that time were often unable to find a significant improvement in survival.12003 Later studies found reductions in mortality when fluorouracil was used in combination with leucovorin for adjuvant treatment of resected colon cancer.12003 Additional research has shown that adding oxaliplatin or irinotecan to fluorouracil/leucovorin improves response rates, progression-free survival, and overall survival.12003
According to the National Cancer Institute (NCI), surgery is the first-line treatment for patients with any stage of colon or rectal cancer.12003 The use of chemotherapy or other systemic therapy after surgery is recommended for recurrent, late-stage, or metastatic disease.12003 Various chemotherapy regimens have been used, including folic acid/fluorouracil/irinotecan, capecitabine/oxaliplatin, and fluorouracil/oxaliplatin.12003 For stage IV or recurrent colon or rectal cancer, surgical resection (based on site of metastasis) and/or systemic therapy (e.g., targeted therapies, palliative chemotherapy) is recommended.12003
The American Society of Clinical Oncology (ASCO) guideline on metastatic colorectal cancer recommends the use of a chemotherapy (doublet or triplet) backbone as first-line therapy for previously untreated, unresectable microsatellite stable (MSS) or proficient mismatch repair (pMMR) metastatic colorectal cancer, in combination with anti-vascular endothelial growth factor (VEGF) antibodies (e.g., bevacizumab).12004 Doublet chemotherapy regimens include folinic acid/fluorouracil/oxaliplatin (FOLFOX) and folinic acid/fluorouracil/irinotecan (FOLFIRI).12004 Triplet chemotherapy includes folinic acid/fluorouracil/oxaliplatin/irinotecan (FOLFOXIRI).12004
Fluorouracil is used for the treatment of patients with adenocarcinoma of the breast.205
According to NCI, treatment options for locally advanced breast cancer include surgery, chemotherapy, radiation therapy, and hormone therapy, with targeted therapies (e.g., trastuzumab) added for locoregional recurrent disease.12000 Guidelines from the ASCO on the selection of optimal adjuvant chemotherapy for early breast cancer recommend adjuvant chemotherapy with an anthracycline-taxane combination.12001 Combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) is recommended as an alternative option to doxorubicin/cyclophosphamide when an anthracycline-taxane combination is contraindicated.12001 This recommendation is based on studies that found similar breast cancer recurrence and mortality rates in patients treated with 4 cycles of doxorubicin-cyclophosphamide (4AC) or CMF; CMF was found to be less effective than anthracycline-based regimens that contained a much higher cumulative dosage than standard 4AC, such as cyclophosphamide-doxorubicin-fluorouracil or cyclophosphamide-epirubicin-fluorouracil.12002
For metastatic disease, treatment options include surgery for metastases, hormone therapy, targeted therapies, chemotherapy, immunotherapy, and radiation.12000 Various chemotherapy agents have been used for metastatic disease, including anthracyclines, cyclophosphamide, taxanes, capecitabine or fluorouracil, vinca alkaloids, and platinum agents.12000
Fluorouracil is used for the treatment of gastric adenocarcinoma.205
Surgical resection is the standard curative treatment for gastric cancer.12006 However, there is a high risk for locoregional and distant recurrence of disease following surgical resection.12006 Thus, perioperative and postoperative (adjuvant) chemotherapy should be considered, particularly in patients with stage II or III disease.12006 Perioperative regimens that have been studied and found to increase overall survival include docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) and epirubicin/ cisplatin/fluorouracil (ECF).12006
According to NCI, for patients with stage IV, inoperable, or recurrent gastric cancers, therapies include a combination of chemotherapy, targeted therapies, immunotherapies, and palliative treatment.12006 First-line palliative systemic therapies for human epidermal growth factor receptor 2 (HER2)-negative tumors include chemotherapy with or without immunotherapy (e.g., fluorouracil or capecitabine with oxaliplatin and nivolumab), triplet chemotherapy regimens (e.g., fluorouracil with either epirubicin and cisplatin, etoposide and leucovorin, or doxorubicin and methotrexate), doublet regimens (e.g., a taxane and either cisplatin or carboplatin, or capecitabine plus oxaliplatin), or single agents (e.g., taxane, fluorouracil, or capecitabine).12006 For HER-2 positive tumors, first-line palliative systemic therapy includes immunotherapy with chemotherapy (nivolumab or trastuzumab with chemotherapy, including cisplatin plus fluorouracil, or capecitabine plus oxaliplatin).12006
Fluorouracil is used for the treatment of patients with pancreatic adenocarcinoma.205
According to NCI, treatment options for pancreatic cancer are based on the clinical stage of the disease and include surgery, chemotherapy, radiation, and chemotherapy with targeted therapy.12009 For patients with resectable or borderline resectable pancreatic cancer, postoperative chemotherapy includes adjuvant FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) or gemcitabine plus capecitabine.12009, 12013 For locally advanced or metastatic pancreatic cancer, current treatment guidelines recommend the use of FOLFIRINOX, gemcitabine-based regimens, fluorouracil/leucovorin/oxaliplatin, and capecitabine-based regimens.12009, 12014, 12015 A Cochrane review that included 11,333 patients with locally advanced, unresectable, or metastatic pancreatic cancer found that combination chemotherapy regimens such as FOLFIRINOX and gemcitabine plus a taxane were associated with a greater improvement in overall survival than gemcitabine monotherapy.12010
Fluorouracil has been used for the treatment of locally advanced esophageal cancer†.12011 Guidelines from the ASCO recognize FLOT as the standard of care for perioperative chemotherapy in patients with locally advanced esophageal carcinoma.12011 This recommendation is based on the findings of a randomized, controlled, open-label phase 2/3 study (FLOT4), which was conducted in 716 patients with advanced, resectable gastric or gastroesophageal junction adenocarcinoma.500 In FLOT4, patients who received perioperative FLOT had improved overall survival compared to patients who received ECF/ECX (epirubicin/cisplatin on day 1 combined with continuous IV fluorouracil or oral capecitabine on days 1-21); severe adverse events between treatment groups were similar.500
Fluorouracil has been used in combination with other chemotherapy agents for the treatment of metastatic or recurrent squamous cell carcinoma of the head and neck†.501 Combination chemotherapy with fluorouracil and cisplatin has long been used for the palliative treatment of recurrent or metastatic head and neck cancer.501 However, resistance can develop in patients receiving such combinations, leading to only modest improvements in overall survival (i.e., median overall survival ranging from 7-12 months).501 Recently, combination therapy which includes standard chemotherapy plus immunotherapy or other treatment options has been implemented to overcome resistance to treatment.501
Fluorouracil in combination with cisplatin has been used concurrently with radiation therapy for the treatment of invasive cervical cancer† .12012
Fluorouracil has been used as second-line therapy for the treatment of biliary tract cancer†.502 A phase 3, open-label, randomized trial (ABC-06) conducted in 162 adults with locally advanced or metastatic biliary tract cancer with documented radiological disease progression following chemotherapy with cisplatin plus gemcitabine compared treatment with FOLFOX plus active symptom control to active symptom control alone.502 At a median follow-up of 21.7 months, overall survival increased in patients who received combination therapy with FOLFOX compared to patients treated with active symptom control alone (median 6.2 versus 5.3 months, respectively).502
Dispensing and Administration Precautions
Fluorouracil is administered IV as a bolus or infusion.205 Do not inject the entire contents of the fluorouracil vial directly.205 The 2.5- or 5-g pharmacy bulk package of fluorouracil is intended for preparation of individual doses of the medication and is not for direct IV infusion; after the vial has been entered, any unused portion should be discarded within 4 hours.205 An established IV line should be used to administer fluorouracil by direct IV injection.205 For IV infusion regimens, the medication should be administered via a central venous catheter using a controlled-infusion device (e.g., pump).205 Store fluorouracil injection in the original carton at 20-25°C; protect from light and do not freeze.205
Pharmacogenomic Considerations
Patients who are intermediate or poor metabolizers of dihydropyrimidine dehydrogenase (DPD) may be at increased risk for severe and sometimes fatal adverse effects with fluoropyrimidines (fluorouracil and capecitabine).205, 700 Genetic DPYD variants associated with reduced DPD enzyme activity (particularly DPYD c.1905+1G>A and c.1679T>G) have been linked to decreased fluorouracil clearance and increased risk for fluorouracil toxicity.700 The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides recommendations for fluoropyrimidine dosing guided by DPYD phenotype.700 For patients who are DPYD intermediate metabolizers (i.e., DPYD activity score of 1 or 1.5), the starting dose should be reduced based on the enzyme activity score; when the activity score is 1, the dose should be reduced by 50% and when the score is 1.5, the dose should be reduced by 25—50%.700 Further dose titration should be guided by toxicity or therapeutic drug monitoring (if available).700
For patients who are DPYD poor metabolizers (i.e., DPYD activity score of 0 or 0.5), it is strongly recommended to avoid use of fluoropyrimidines.700 In patients with an activity score of 0.5 who do not have suitable alternative therapeutic options, fluoropyrimidines should be administered at a markedly reduced dose (i.e., estimated via phenotyping test or <25% of the normal starting dose), with therapeutic drug monitoring completed as early as possible.700 Consult the CPIC guideline for additional details.700
Dosage and dosage schedules of fluorouracil should be individualized based on the tumor type, specific regimen, clinical response, and concomitant comorbidities.205 Clinicians should consult published protocols for the dosage of fluorouracil and other chemotherapeutic agents and the method and sequence of administration.
If fluorouracil is administered by direct IV injection in combination with leucovorin or levoleucovorin for the treatment of adenocarcinoma of the colon and rectum, the manufacturers of fluorouracil recommend a dosage of 500 mg/m2 on days 1, 8, 15, 22, 29, and 36 of each 8-week cycle.205
If fluorouracil is administered by IV infusion in combination with leucovorin or levoleucovorin (plus oxaliplatin or irinotecan) for the treatment of adenocarcinoma of the colon and rectum, the manufacturers of fluorouracil recommend a dosage of 400 mg/m2 by direct IV injection on day 1 followed by 2400-3000 mg/m2 by continuous IV infusion over 46 hours every 14 days.205
Monthly Direct IV Injection (“Bolus”) Schedule (Mayo Clinic Regimen)
A monthly regimen administered by direct IV injection is leucovorin 20 mg/m2 IV or an equivalent dose of levoleucovorin (10 mg/m2 IV) followed by IV fluorouracil 425 mg/m2; fluorouracil and either leucovorin or levoleucovorin are administered daily for 5 consecutive days.286, 289, 395, 12003 The regimen is repeated at 4-week intervals for 2 additional courses; thereafter, the regimen may be repeated at intervals of 4-5 weeks provided toxicity from the previous course has resolved completely.286, 289, 395, 12003 This regimen is frequently administered for a total of 6 cycles in the adjuvant setting.12003
Alternatively, leucovorin 200 mg/m2 or an equivalent dose of levoleucovorin (100 mg/m2) may be administered by slow IV injection (over a minimum of 3 minutes) and followed by IV fluorouracil 370 mg/m2; fluorouracil and either leucovorin or levoleucovorin are administered daily for 5 consecutive days.286, 395, 397 The regimen is repeated at 4-week intervals for 2 additional courses; thereafter, the regimen may be repeated at intervals of 4-5 weeks provided toxicity from the previous course has resolved completely.286, 395, 397
Adjust fluorouracil dosage in subsequent courses according to tolerance; 395 reduce daily fluorouracil dosage by 20% for moderate hematologic or GI toxicity in prior course and by 30% for severe toxicity 289, 395 (leucovorin or levoleucovorin dosage is not adjusted 395 ).
May increase fluorouracil dosage by 10% if no toxicity occurred in the prior course. 395
Weekly IV Infusion Schedule (Roswell Park Regimen)
The weekly regimen administered by IV infusion consists of 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.12003 Both medications are administered weekly for 6 consecutive weeks, followed by a 2-week rest; cycles are repeated every 8 weeks for a total of 4 courses in the adjuvant setting.12003
Bimonthly Infusion Schedule (Modified deGramont Regimen)
The bimonthly regimen consists of 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., a total of 3000 mg/m2 by continuous IV infusion over 46 hours); cycles are repeated every 2 weeks.391
Combination Therapy with Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX)
Combined therapy with fluorouracil, oxaliplatin, and leucovorin is administered over 2 consecutive days (FOLFOX-4).411, 12003 On day 1, oxaliplatin 85 mg/m2 and leucovorin 200 mg/m2 are administered concurrently (in separate containers using a Y-type administration set) by IV infusion over 2 hours.411, 12003 Fluorouracil 400 mg/m2 is then administered by direct IV injection, followed by fluorouracil 600 mg/m2 administered as an IV infusion over 22 hours.411, 12003 On day 2, leucovorin 200 mg/m2 is administered by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 administered by direct IV injection and then fluorouracil 600 mg/m2 administered as an IV infusion over 22 hours.441, 12003 This regimen is repeated every 2 weeks.411
Combined therapy with fluorouracil, oxaliplatin, and leucovorin also has been administered as 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 of each 2-week cycle (FOLFOX-6).12003
Combination Therapy with Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI)
When fluorouracil is administered in combination with leucovorin and irinotecan (FOLFIRI) for the treatment of colorectal cancer, irinotecan 180 mg/m2 and leucovorin 400 mg/m2 are 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 of each 2-week cycle.418, 12003
Combination Therapy with Fluorouracil, Leucovorin, Oxaliplatin and Irinotecan (FOLFOXIRI)
When fluorouracil is administered in combination with leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) for the treatment of colorectal cancer, irinotecan 165 mg/m2 is administered 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 of each 2-week cycle.441, 12003
Dosage Modification for Mayo Clinic and Roswell Park Regimens
Dosage of fluorouracil in subsequent courses of therapy should be adjusted according to patient tolerance of the prior treatment course; dosage of leucovorin or levoleucovorin in subsequent courses is not adjusted because of toxicity.286, 395 Daily fluorouracil dosage generally is reduced by 20% in patients who experienced moderate hematologic or GI toxicity in the prior course and by 30% in those patients who experienced severe toxicity.286 For patients who experienced no toxicity in the prior course of therapy, the dosage of fluorouracil may be increased by 10%.286
Various fluorouracil-containing combination chemotherapy regimens have been used in the treatment of breast cancer, and published protocols should be consulted for dosages and the method and sequence of administration.
When fluorouracil is combined with a cyclophosphamide-based regimen for the treatment of breast cancer, the manufacturers of fluorouracil recommend a dosage of 500 or 600 mg/m2 IV on days 1 and 8 of each 28-day cycle for a total of 6 cycles.205
One commonly employed regimen (CMF) for the treatment of early breast cancer includes a fluorouracil dosage of 600 mg/m2 IV on days 1 and 8 of each cycle, combined with cyclophosphamide 100 mg/m2 orally on days 1 through 14 of each cycle, and methotrexate 40 mg/m2 IV on days 1 and 8 of each cycle.320, 321 In patients older than 60 years of age, the initial fluorouracil dosage was reduced to 400 mg/m2 IV and the initial methotrexate dosage was reduced to 30 mg/m2 IV.321 Dosage also was reduced if myelosuppression developed.320, 321 Cycles generally were repeated monthly (i.e., allowing a 2-week rest period between cycles) for a total of 6-12 cycles (i.e., 6-12 months of therapy).320, 321
When fluorouracil is combined with a platinum-based regimen for the treatment of gastric adenocarcinoma, the manufacturers of fluorouracil recommend a dosage of 200-1000 mg/m2 as a continuous IV infusion over 24 hours.205 Clinicians should consult published protocols for the frequency of fluorouracil dosing and duration of each cycle for the specific regimen.
When fluorouracil is used in combination with leucovorin or as a component of a multidrug regimen that includes leucovorin for the treatment of pancreatic adenocarcinoma, the manufacturers of fluorouracil recommend a dosage of 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.205
Dosage Modifications for Toxicity
If grade 3 or 4 diarrhea or mucositis, grade 4 myelosuppression, or grade 2 or 3 palmar-plantar erythrodysesthesia (hand-foot syndrome) occurs, withhold fluorouracil.205 When the toxicity has resolved or improved to grade 1, resume fluorouracil at a reduced dosage.205
Withhold fluorouracil 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.205 Therapy with the medication also should be withheld if hyperammonemic encephalopathy or neurologic effects (i.e., acute cerebellar syndrome, confusion, disorientation, ataxia, visual disturbance) develop.205 The manufacturers state there is no recommended dosage for resumption of fluorouracil following development of cardiotoxicity, hyperammonemic encephalopathy, or neurologic effects.205
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.205
The manufacturer makes no specific dosage recommendations for patients with renal impairment.205
The manufacturer makes no specific dosage recommendations for geriatric patients.205
Pharmacogenomics of Fluorouracil-induced Serious Reactions from Dihydropyrimidine Dehydrogenase (DPD) Deficiency
Dihydropyrimidine dehydrogenase, encoded by the DPYD gene, is responsible for the catabolism of >80% of fluorouracil.205 Patients with certain homozygous or certain compound heterozygous mutations in the DPYD gene resulting in a complete or near complete absence of DPD activity (i.e., DPYD poor metabolizers) are at increased risk for acute early-onset toxicity and severe, life-threatening, or fatal toxicity (e.g., mucositis, diarrhea, neutropenia, neurotoxicity) caused by fluorouracil; patients with partial DPD activity (i.e., DPYD intermediate metabolizers) also may be at increased risk for severe, life-threatening, or fatal toxicity.205, 700 Fluorouracil is not recommended for use in patients with known homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency.205 Withhold or permanently discontinue fluorouracil in patients experiencing acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity.205 No dosage of fluorouracil has been proven safe for patients with complete absence of DPD activity, and there are insufficient data to support dosage recommendations for those with partial DPD activity.205 Consider testing patients for genetic variants of DPYD prior to initiating treatment with fluorouracil.205 However, serious adverse reactions can still occur even if no variants are identified.205
Genetic DPYD variants associated with reduced DPD enzyme activity (particularly DPYD c.1905+1G>A and c.1679T>G) have been linked to decreased fluorouracil clearance and increased risk for fluorouracil toxicity.700 The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides recommendations for fluoropyrimidine dosing guided by DPYD phenotype.700 Dosage adjustments are recommended for patients who are DPYD intermediate metabolizers, and fluoropyrimidines should be avoided in patients who are DPYD poor metabolizers.700 Consult the CPIC guideline for more details and definitions of DPYD phenotypes based on genotypes.700
Based on postmarketing reports, fluorouracil can cause cardiotoxicity, including angina, myocardial infarction or ischemia, arrhythmia, and heart failure.205 Patients with coronary artery disease and those receiving the medication via continuous infusion rather than IV bolus may be at higher risk for cardiotoxicity.205 If cardiotoxicity develops, withhold fluorouracil.205 The risks of resuming fluorouracil in patients following resolution of cardiotoxicity have not been established.205
Based on postmarketing reports, fluorouracil can cause hyperammonemic encephalopathy, even in patients without liver disease or other identifiable causes.205 Signs and symptoms of hyperammonemic encephalopathy (e.g., altered mental status, confusion, disorientation, ataxia, or coma) in the presence of a concomitant elevated serum ammonia level have occurred within 72 hours of initiating fluorouracil.205 If hyperammonemic encephalopathy occurs, withhold fluorouracil and initiate ammonia-lowering therapy.205 The risks of resuming fluorouracil in patients following resolution of hyperammonemic encephalopathy have not been established.205
Based on postmarketing reports, fluorouracil can cause neurologic toxicity.205 Symptoms of neurologic toxicity include confusion, disorientation, ataxia, visual disturbances, and acute cerebellar syndrome.205 If neurologic toxicity occurs, withhold fluorouracil.205 The risks of resuming fluorouracil in patients following resolution of neurologic toxicity have not been established.205
Fluorouracil can cause severe diarrhea.205 If grade 3 or 4 diarrhea occurs, withhold fluorouracil until resolved or decreased to grade 1 intensity, then resume therapy at a reduced dosage.205 Administer fluids, electrolyte replacement, or anti-diarrheal therapy as necessary.205
Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome)
Fluorouracil can cause palmar-plantar erythrodysesthesia syndrome, which is also known as hand-foot syndrome.205 Symptoms of hand-foot syndrome include a tingling sensation, pain, swelling, and erythema with tenderness and desquamation.205 Hand-foot syndrome occurs most commonly when fluorouracil is administered via continuous infusion and has been reported to occur more frequently in patients with previous exposure to chemotherapy.205 Hand-foot syndrome has generally been observed 8-9 weeks after administration of fluorouracil, but may occur earlier.205 Initiate supportive measures to treat symptoms of hand-foot syndrome.205 If grade 2 or 3 hand-foot syndrome occurs, withhold treatment; resume fluorouracil at a reduced dosage following complete resolution of symptoms or reduction in severity to grade 1.205
Fluorouracil can cause severe and fatal myelosuppression, including neutropenia, thrombocytopenia, and anemia.205 The nadir in neutrophil counts commonly occurs between 9-14 days after administration of fluorouracil.205 Obtain a CBC prior to each treatment cycle, weekly if administered on a weekly or similar schedule, and as needed.205 If grade 4 myelosuppression occurs, withhold treatment; resume fluorouracil at a reduced dosage following resolution or reduction in severity to grade 1.205
Fluorouracil can cause mucositis, stomatitis, or esophagopharyngitis, which may lead to mucosal sloughing or ulceration.205 These symptoms occur with a higher incidence when fluorouracil is administered via IV bolus.205 If grade 3 or 4 mucositis occurs, withhold treatment; resume fluorouracil at a reduced dosage following resolution or reduction in severity to grade 1.205
Increased Risk of Elevated International Normalized Ratio (INR) with Warfarin
Clinically significant elevations in coagulation parameters can occur when fluorouracil is used concomitantly with warfarin.205 Closely monitor INR or prothrombin time in patients receiving concomitant coumarin-derivative anticoagulants and adjust the anticoagulant dose as appropriate.205
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action, fluorouracil can cause fetal harm when administered to a pregnant patient.205 There are no adequate and well-controlled studies with fluorouracil in pregnant females.205 In animal studies, administration of fluorouracil to rats and mice during selected periods of organogenesis, at doses lower than a human dose of 12 mg/kg, caused embryolethality and teratogenicity.205 Additionally, animal studies have shown that fluorouracil may impair fertility in females and males of reproductive potential.205
If fluorouracil is used during pregnancy or the patient becomes pregnant while taking it, apprise the patient of the potential hazard to a fetus.205 (See Females and Males of Reproductive Potential under Cautions.)
Fluorouracil may cause fetal harm when administered to pregnant females.205 The medication has been shown to be embryotoxic and teratogenic in animals at dosages lower than a human dose of 12 mg/kg.205 Fetal malformations included cleft palate, skeletal defects, and deformed appendages, paws, and tails.205 In monkeys, doses greater than an approximate human dose of 12 mg/kg resulted in abortion.205
There are no adequate and controlled studies using fluorouracil in pregnant females.205 If the medication is used during pregnancy or if the patient becomes pregnant while receiving fluorouracil, the patient should be informed of the potential hazard to the fetus.205
It is not known whether fluorouracil or its metabolites are distributed into milk.205 Because many medications are distributed into human milk and because of the potential for serious adverse reactions to fluorouracil in nursing infants, a decision should be made whether to discontinue nursing or the medication, taking into account the importance of the medication to the nursing mother.205
Females and Males of Reproductive Potential
Based on its mechanism of action, fluorouracil may cause fetal harm when administered to a pregnant females.205 Fluorouracil may also damage sperm in male patients.205 Females of childbearing potential and males with female partners of childbearing potential should be advised to use effective contraceptive methods during fluorouracil therapy and for up to 3 months after the last dose.205
Based on animal data, male and female fertility may be impaired while receiving fluorouracil.205 Following intraperitoneal administration of fluorouracil at doses greater than or equal to 1.7 times the human dose of 12 mg/kg in male rats, chromosomal aberrations in spermatogonia were induced; spermatogonial differentiation also was inhibited, resulting in transient infertility.205 Following intraperitoneal administration of fluorouracil at doses greater than or equal to 0.33 times the human dose of 12 mg/kg during the preovulatory phases of oogenesis in female rats, fetotoxicity, decreased fertile matings, and increased preimplantation loss were observed.205
Safety and effectiveness of fluorouracil have not been established in pediatric patients.205
Reported clinical experience with fluorouracil has not identified any differences in safety or effectiveness between geriatric patients and younger adults.205
No pharmacokinetic data are available in patients with hepatic impairment.205
No pharmacokinetic data are available in patients with renal impairment.205
Reported adverse effects for fluorouracil come from postmarketing reports and include pancytopenia, gastrointestinal ulceration, nausea, vomiting, anaphylaxis and generalized allergic reactions, nystagmus, headache, dry skin, fissuring, photosensitivity (manifested by erythema or increased skin pigmentation), vein pigmentation, lacrimal duct stenosis, visual changes, lacrimation, photophobia, euphoria, thrombophlebitis, epistaxis, and nail changes.205
Drugs Metabolized by Hepatic Microsomal Enzymes
Fluorouracil or its metabolites may inhibit cytochrome P-450 (CYP) isoenzyme 2C9.205
When fluorouracil was administered concomitantly with warfarin, clinically important elevations in coagulation parameters have been reported.205 Although concomitant use of fluorouracil with warfarin has not been specifically studied, altered coagulation parameters (e.g., increased international normalized ratio [INR], prothrombin time [PT]) were accompanied by increased systemic exposure to warfarin in patients receiving the prodrug of fluorouracil (capecitabine) and concomitant warfarin therapy.205 If fluorouracil is administered with a coumarin anticoagulant, the INR or PT should be closely monitored, and anticoagulant dosage adjusted accordingly.205
Although the precise mechanisms of action of fluorouracil have not been fully elucidated, the main mechanism is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5-10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex, which inhibits the formation of thymidylate from uracil, thereby interfering with DNA synthesis.358 In addition, 5-fluorouridine-5'triphosphate (FUTP) can be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis.358
Fluorouracil is distributed throughout the body into intestinal mucosa, bone marrow, liver, CSF, and brain tissue.205, It is not known whether the medication or its metabolites are distributed into human milk.205 Following direct IV injection, the plasma elimination half-life ranges from 8-20 minutes.205 The major portion of the medication is degraded in the liver.205 Following direct IV injection of fluorouracil, 5-20% of the dose is excreted in urine as intact drug within 6 hours.205 The metabolites (e.g., urea, α-fluoro-β-alanine) are excreted in urine over 3-4 hours.205
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV use | 50 mg/mL* | Fluorouracil Injection | |
50 mg/mL (2.5 or 5 g) pharmacy bulk package* | Fluorouracil Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
205. Accord Healthcare Inc. Fluorouracil injection prescribing information. Raleigh, NC; 2024 Mar.
286. Fresenius Kabi. Leucovorin calcium injection prescribing information. Lake Zurich, IL; 2010 May.
289. Lederle. Combination chemotherapy with leucovorin calcium and 5-fluorouracil. Pearl River, NY; 1992 Mar.
320. Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med . 1976; 294:405-10. [PubMed 1246307]
321. Bonadonna G, Valagussa P, Moliterni A et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med . 1995; 332:901-6. [PubMed 7877646]
358. Pinedo HM, Peters GFJ. Fluorouracil: biochemistry and pharmacology. J Clin Oncol . 1988; 6:1653-64. [PubMed 3049954]
391. Tournigand C, Cervantes A, Figer A et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006; 24:394-400
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