Version May 2024
Anal carcinoma (off-label use):
Localized disease: IV: 1,000 mg/m2/day continuous infusion days 1 to 4 (total dose is 4,000 mg/m2) and days 29 to 32 (total dose is 4,000 mg/m2) (in combination with mitomycin and radiation therapy) (Ref).
Advanced or metastatic disease:
In combination with cisplatin: IV: 750 mg/m2/day continuous infusion days 1 to 5 (total dose/cycle is 3,750 mg/m2) every 4 weeks (in combination with cisplatin); patients received a median of 4 cycles in the study (Ref).
FOLFCIS regimen: IV: 400 mg/m2 bolus on day 1, followed by 1,000 mg/m2/day continuous infusion days 1 and 2 (total dose/cycle [bolus and continuous infusion] is 2,400 mg/m2) every 14 days until disease progression or unacceptable toxicity (Ref).
Biliary tract cancer, advanced (off-label use):
FOLFOX regimen: IV: 400 mg/m2 bolus on day 1, followed by 2,400 mg/m2 over 46 hours (as a continuous infusion) every 2 weeks (total dose/cycle [bolus and continuous infusion] is 2,800 mg/m2; in combination with levoleucovorin and oxaliplatin) for up to 12 cycles (Ref).
Bladder cancer, muscle-invasive (off-label use): IV: 500 mg/m2/day continuous infusion during radiation therapy fractions 1 to 5 and 16 to 20 (total dose/each 5-day course is 2,500 mg/m2; in combination with mitomycin and radiation therapy) (Ref).
Breast cancer:
CEF or FEC regimen: IV: 500 mg/m2 on days 1 and 8 every 28 days (in combination with cyclophosphamide and epirubicin) for 6 cycles (Ref).
CMF regimen: IV: 600 mg/m2 on days 1 and 8 every 28 days (in combination with cyclophosphamide and methotrexate) for 6 cycles (Ref).
Breast cancer, early, HER2-positive:
FEC-THP regimen: IV: 500 mg/m2 on day 1 every 3 weeks (in combination with epirubicin and cyclophosphamide) as neoadjuvant therapy for 3 cycles, followed by 3 cycles of neoadjuvant docetaxel, trastuzumab, and pertuzumab (Ref). Refer to protocol for further information.
THP-FEC-H regimen: IV:600 mg/m2 on day 1 every 3 weeks (in combination with epirubicin and cyclophosphamide) as adjuvant therapy for 3 cycles, followed by trastuzumab to complete 1 year of treatment; neoadjuvant trastuzumab, pertuzumab, and docetaxel were administered for 4 cycles prior to surgery (Ref). Refer to protocol for further information.
Cervical cancer (off-label use): IV: 1,000 mg/m2/day continuous infusion days 1 to 4 (total dose/cycle is 4,000 mg/m2; in combination with cisplatin and radiation therapy) every 3 weeks for 3 cycles (Ref).
Colorectal cancer: IV: 400 mg/m2 bolus on day 1, followed by 2,400 to 3,000 mg/m2 over 46 hours (as a continuous infusion) every 2 weeks (in combination with leucovorin ± either oxaliplatin or irinotecan) or
Preoperative chemoradiation (in patients with clinical stage II or III rectal cancer): IV: 225 mg/m2/day continuous infusion 5 days per week for a total of 5 weeks (total dose/week is 1,125 mg/m2; in combination with radiation therapy) (Ref).
Roswell Park regimen: IV: 500 mg/m2 (bolus) on days 1, 8, 15, 22, 29, and 36 (1 hour after the start of leucovorin) every 8 weeks (in combination with leucovorin) for 4 cycles (Ref).
FOLFOX regimens: Note: Multiple FOLFOX variations exist and may be administered in combination with other agents for the treatment of colorectal cancer. FOLFOX regimens may also be administered in combination with bevacizumab (Ref), cetuximab (Ref), or panitumumab (Ref). Refer to institutional guidelines and/or protocols for further information.
FOLFOX6 and mFOLFOX6 regimen: IV: 400 mg/m2 bolus on day 1, followed by 2,400 mg/m2 over 46 hours (as a continuous infusion) every 2 weeks (in combination with leucovorin and oxaliplatin) until disease progression or unacceptable toxicity occurs (Ref).
mFOLFOX7 regimen: IV: 2,400 mg/m2 over 46 hours (as a continuous infusion) every 2 weeks (in combination with leucovorin and oxaliplatin) until disease progression or unacceptable toxicity (Ref).
FOLFIRI regimen: IV: 400 mg/m2 bolus on day 1, followed by 2,400 mg/m2 over 46 hours (as a continuous infusion) every 2 weeks (in combination with leucovorin and irinotecan) until disease progression or unacceptable toxicity occurs; refer to protocol for further information (Ref). Note: FOLFIRI regimens may be also administered in combination with bevacizumab (Ref), cetuximab (Ref), panitumumab (Ref), ramucirumab (Ref), or ziv-aflibercept (Ref); refer to protocols for further information.
FOLFOXIRI regimen: IV: 3,200 mg/m2 over 48 hours (as a continuous infusion) every 14 days (in combination with leucovorin, oxaliplatin, and irinotecan) until disease progression or unacceptable toxicity up to a maximum of 12 cycles (Ref); may also be used in combination with bevacizumab (Ref); refer to protocol for further information or 3,000 mg/m2 over 48 hours (as a continuous infusion) every 14 days (in combination with leucovorin, oxaliplatin, irinotecan, and panitumumab) until disease progression or resection for up to a maximum of 12 preoperative cycles in patients with wild-type RAS metastatic colorectal cancer; after resection, patients received the same regimen as adjuvant therapy for a total of 12 perioperative cycles (Ref).
FLOX regimen (off-label dosing) : IV: 500 mg/m2 bolus on days 1, 8, 15, 22, 29, and 36 (1 hour after the start of leucovorin) every 8 weeks (in combination with leucovorin and oxaliplatin) for 3 cycles (Ref).
Adjuvant therapy duration; completely resected stage 3 colon cancer (off label):
Low risk (T1, T2, or T3 and N1): A duration of therapy of 3 or 6 months of fluoropyrimidine/oxaliplatin-based adjuvant chemotherapy may be offered (Ref).
High risk (T4 and/or N2): A duration of therapy of 6 months of fluoropyrimidine/oxaliplatin-based adjuvant chemotherapy should be offered (Ref). In a pooled analysis of 6 phase 3 studies, superior disease-free survival has been demonstrated with 6 months (compared to 3 months) of adjuvant FOLFOX therapy in the subgroup of patients with T4 and/or N2 stage 3 colon cancer (Ref).
Esophageal cancer (off-label use):
CF regimen (esophageal or gastroesophageal junction cancer): IV: 1,000 mg/m2/day continuous infusion days 1 to 4 (total dose/cycle is 4,000 mg/m2) every 28 days (in combination with cisplatin and concurrent radiation) for 4 cycles, followed by 2 additional cycles after a 4-week rest following completion of radiation (Ref) or 1,000 mg/m2/day continuous infusion days 1 to 4 (total dose is 4,000 mg/m2) and days 29 to 32 (total dose is 4,000 mg/m2) of a 35-day treatment cycle (preoperative chemoradiation; in combination with cisplatin) (Ref) or 1,000 mg/m2/day continuous infusion days 1 to 4 (total dose/cycle is 4,000 mg/m2) every 3 weeks for 2 cycles (neoadjuvant chemotherapy prior to surgery; in combination with cisplatin; for adenocarcinoma) (Ref).
FLO regimen (locally advanced or metastatic gastroesophageal junction adenocarcinoma): IV: 2,600 mg/m2 continuous infusion over 24 hours on day 1 every 2 weeks (in combination with leucovorin and oxaliplatin) until disease progression or unacceptable toxicity (Ref).
FLOT regimen (locally advanced, resectable gastroesophageal junction adenocarcinoma): IV: 2,600 mg/m2 continuous infusion over 24 hours on day 1 every 2 weeks (in combination with leucovorin, oxaliplatin, and docetaxel) for 4 preoperative cycles and 4 postoperative cycles (Ref).
FOLFOX4 regimen (chemoradiotherapy for locally advanced, recurrent, or metastatic disease): IV: 400 mg/m2 bolus, followed by 600 mg/m2 over 22 hours, repeated for 2 consecutive days (total dose/cycle [bolus and continuous infusion] is 2,000 mg/m2) every 2 weeks, in combination with leucovorin and oxaliplatin and radiation for 3 cycles, then without radiation for 3 more cycles (Ref).
FOLFOX/nivolumab (unresectable advanced or metastatic esophageal or gastroesophageal junction adenocarcinoma): IV: 400 mg/m2 bolus on day 1, followed by 1,200 mg/m2/day on days 1 and 2 (as a continuous infusion) every 2 weeks (total dose/cycle [bolus and continuous infusion] is 2,800 mg/m2; in combination with leucovorin, oxaliplatin, and nivolumab) until disease progression or unacceptable toxicity (Ref).
mFOLFOX6 (metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or gastroesophageal junction): IV: 400 mg/m2 bolus on day 1, followed by 2,400 mg/m2 over 46 to 48 hours (as a continuous infusion) every 2 weeks (total dose/cycle [bolus and continuous infusion] is 2,800 mg/m2; in combination with leucovorin and oxaliplatin) until disease progression or unacceptable toxicity (Ref).
Nivolumab/cisplatin/fluorouracil (esophageal squamous cell carcinoma): IV: 800 mg/m2/day as a continuous infusion on days 1 to 5 (total dose/cycle is 4,000 mg/m2) every 4 weeks until disease progression or unacceptable toxicity; patients could continue nivolumab for up to 2 years (Ref). Refer to protocol for further details.
Pembrolizumab/cisplatin/fluorouracil (esophageal or gastroesophageal junction cancer): IV: 800 mg/m2/day as a continuous infusion on days 1 to 5 every 3 weeks (total dose/cycle is 4,000 mg/m2); continue pembrolizumab and fluorouracil until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref). Refer to protocol for further details.
Pembrolizumab/trastuzumab/cisplatin/fluorouracil (HER2-positive gastroesophageal junction adenocarcinoma): IV: 800 mg/m2/day as a continuous infusion on days 1 to 5 every 3 weeks (total dose/cycle is 4,000 mg/m2); continue until disease progression or unacceptable toxicity or (in patients without disease progression) for up to 24 months (Ref).
TCF or DCF or mDCF regimen (advanced gastroesophageal junction adenocarcinoma): IV: 400 mg/m2 bolus on day 1, followed by 1,000 mg/m2/day as a continuous infusion on days 1 and 2 every 2 weeks (total dose/cycle [bolus and continuous infusion] is 2,400 mg/m2; in combination with docetaxel, leucovorin, and cisplatin; mDCF regimen) until disease progression or unacceptable toxicity (Ref) or 750 mg/m2/day continuous infusion days 1 to 5 (total dose/cycle is 3,750 mg/m2) every 3 weeks (in combination with docetaxel and cisplatin) until disease progression or unacceptable toxicity occurs (Ref).
ToGA regimen (HER2-positive; locally advanced, recurrent, or metastatic gastroesophageal junction adenocarcinoma): IV: 800 mg/m2/day continuous infusion days 1 to 5 (total dose/cycle is 4,000 mg/m2) every 3 weeks (in combination with cisplatin and trastuzumab) for 6 cycles; continue trastuzumab until disease progression or unacceptable toxicity occurs (Ref).
Treatment of advanced or metastatic disease: Treatment with doublet, rather than triplet, chemotherapy may be preferred in the palliative setting due to increased toxicity (without clear benefit) with triplet regimens (Ref).
Gastric cancer: IV: Continuous infusion (as part of a platinum-containing regimen); the dose, duration, and frequency of each cycle varies based on the regimen.
FLO regimen (locally advanced or metastatic gastric adenocarcinoma): IV: 2,600 mg/m2 continuous infusion over 24 hours on day 1 every 2 weeks (in combination with leucovorin and oxaliplatin) until disease progression or unacceptable toxicity (Ref).
FLOT regimen (locally advanced, resectable gastric adenocarcinoma): IV: 2,600 mg/m2 continuous infusion over 24 hours on day 1 every 2 weeks (in combination with leucovorin, oxaliplatin, and docetaxel) for 4 preoperative cycles and 4 postoperative cycles (Ref).
FOLFOX/nivolumab (unresectable advanced or metastatic gastric adenocarcinoma): IV: 400 mg/m2 bolus on day 1, followed by 1,200 mg/m2/day on days 1 and 2 (as a continuous infusion) every 2 weeks (total dose/cycle [bolus and continuous infusion] is 2,800 mg/m2; in combination with leucovorin, oxaliplatin, and nivolumab) until disease progression or unacceptable toxicity (Ref).
Pembrolizumab/trastuzumab/cisplatin/fluorouracil (HER2-positive gastric adenocarcinoma): IV: 800 mg/m2/day as a continuous infusion on days 1 to 5 every 3 weeks (total dose/cycle is 4,000 mg/m2); continue until disease progression or unacceptable toxicity or (in patients without disease progression) for up to 24 months (Ref).
TCF or DCF or mDCF regimen (advanced gastric adenocarcinoma): IV: 400 mg/m2 bolus on day 1, followed by 1,000 mg/m2/day as a continuous infusion on days 1 and 2 every 2 weeks (total dose/cycle [bolus and continuous infusion] is 2,400 mg/m2; in combination with docetaxel, leucovorin, and cisplatin; mDCF regimen) until disease progression or unacceptable toxicity (Ref) or 750mg/m2/day continuous infusion days 1 to 5 (total dose/cycle is 3,750 mg/m2) every 3 weeks (in combination with docetaxel and cisplatin) until disease progression or unacceptable toxicity occurs (Ref).
ToGA regimen (HER2-positive; locally advanced, recurrent, or metastatic gastric adenocarcinoma): IV: 800 mg/m2/day continuous infusion days 1 to 5 (total dose/cycle is 4,000 mg/m2) every 3 weeks (in combination with cisplatin and trastuzumab) for 6 cycles; continue trastuzumab until disease progression or unacceptable toxicity occurs (Ref).
Treatment of advanced or metastatic disease: Treatment with doublet, rather than triplet, chemotherapy is preferred in the palliative setting due to increased toxicity (without clear benefit) with triplet regimens (Ref).
Glaucoma surgery, adjunctive therapy (off-label use):
Intraoperative topical application: Ophthalmic: Apply sponge soaked in fluorouracil 50 mg/mL for 5 minutes (Ref).
Postoperative subconjunctival injection: Ophthalmic: 5 mg once daily for 10 days or 5 mg once daily for 1 week, then every other day the next week for a total of 10 doses (Ref).
Head and neck cancer, advanced, squamous cell (off-label use):
Platinum-Fluorouracil (CF) regimen: IV: 1,000 mg/m2/day continuous infusion days 1 to 4 (total dose/cycle is 4,000 mg/m2) every 3 weeks (in combination with cisplatin) for at least 6 cycles (Ref) or 1,000 mg/m2/day continuous infusion days 1 to 4 (total dose/cycle is 4,000 mg/m2) every 4 weeks (in combination with carboplatin) (Ref) or 600 mg/m2/day continuous infusion days 1 to 4, 22 to 25, and 43 to 46 (total dose for each 4-day course is 2,400 mg/m2; in combination with carboplatin and radiation) (Ref).
TPF regimen: IV: 1,000 mg/m2/day continuous infusion days 1 to 4 (total dose/cycle is 4,000 mg/m2) every 3 weeks (in combination with docetaxel and cisplatin) for 3 cycles, and followed by chemoradiotherapy (Ref) or 750 mg/m2/day continuous infusion days 1 to 5 (total dose/cycle is 3,750 mg/m2) every 3 weeks (in combination with docetaxel and cisplatin) for up to 4 cycles, followed by radiation in patients without progressive disease (Ref).
Platinum, fluorouracil, and cetuximab regimen: IV: 1,000 mg/m2/day continuous infusion days 1 to 4 (total dose/cycle is 4,000 mg/m2) every 3 weeks (in combination with cetuximab and either cisplatin or carboplatin) for a total of up to 6 cycles (Ref).
Pembrolizumab-fluorouracil-platinum regimen: IV: 1,000 mg/m2/day continuous infusion days 1 to 4 (total dose/cycle is 4,000 mg/m2) every 3 weeks (in combination with either carboplatin or cisplatin and pembrolizumab) for 6 cycles, followed by up to 24 months of pembrolizumab monotherapy (Ref).
Neuroendocrine tumors: Pancreatic (off-label use): IV: 400 mg/m2/day (bolus) days 1 to 5 every 28 days (in combination with doxorubicin and streptozocin) for at least 4 cycles and until disease progression or unacceptable toxicity occurs (Ref).
Pancreatic cancer:
Potentially curable disease, adjuvant therapy: Note: American Society of Clinical Oncology (ASCO) guidelines recommend 6 months of adjuvant therapy; if preoperative chemotherapy therapy was received, a total of 6 months of adjuvant therapy (including the preoperative regimen) is recommended (Ref).
mFOLFIRINOX regimen: IV: 2,400 mg/m2 as a continuous infusion over 46 hours every 14 days (in combination with leucovorin, irinotecan, and oxaliplatin) for 24 weeks (Ref). According to ASCO guidelines, mFOLFIRINOX is the preferred first-line adjuvant regimen for potentially curable disease (Ref).
Chemoradiation therapy (off-label dosing): IV: 250 mg/m2/day continuous infusion for 3 weeks prior to and then throughout radiation therapy; an additional 12 weeks of fluorouracil (as a continuous infusion, 4 weeks on and 2 weeks off for 2 cycles) was administered beginning 3 to 5 weeks after completion of chemoradiation (Ref). Note: According to ASCO guidelines for potentially curable pancreatic cancer, adjuvant chemoradiation therapy may be considered for patients not receiving preoperative therapy and who present with positive margins (microscopically) following surgery and/or node-positive disease after completion of 4 to 6 months of systemic adjuvant chemotherapy (Ref).
Advanced or metastatic disease:
Fluorouracil with irinotecan (liposomal): I V: 2,400 mg/m2 (as a continuous infusion) over 46 hours every 14 days (in combination with leucovorin and irinotecan [liposomal]) until disease progression or unacceptable toxicity (Ref).
FOLFIRINOX regimen: IV: 400 mg/m2 bolus on day 1, followed by 2,400 mg/m2 (as a continuous infusion) over 46 hours every 14 days (in combination with leucovorin, irinotecan, and oxaliplatin) until disease progression or unacceptable toxicity occurs for a recommended 12 cycles (Ref).
mFOLFOX regimen (second-line therapy): IV: 2,000 mg/m2 (as a continuous infusion) over 46 hours every 2 weeks (in combination with leucovorin and oxaliplatin) until disease progression or unacceptable toxicity (Ref).
OFF regimen (second-line therapy): IV: 2,000 mg/m2/day continuous infusion over 24 hours on days 1, 8, 15, and 22 every 6 weeks (in combination with oxaliplatin and leucovorin) until disease progression or unacceptable toxicity (Ref).
Penile cancer, advanced, squamous cell (off-label use): IV: 800 to 1,000 mg/m2/day continuous infusion for 4 days (total dose/cycle is 3,200 to 4,000 mg/m2) every 21 days (in combination with cisplatin) (Ref) or 1,000 mg/m2/day continuous infusion on days 1 to 4 (total dose is 4,000 mg/m2) and days 29 to 32 (total dose is 4,000 mg/m2) (in combination with mitomycin and radiation) (Ref).
Small bowel adenocarcinoma, advanced unresectable or metastatic (off-label use): Note: Ampullary adenocarcinomas were excluded from these studies (Ref).
FOLFIRI regimen (following progression on a platinum-based regimen): IV: 400 mg/m2 bolus on day 1, followed by 2,400 mg/m2 over 46 hours (as a continuous infusion) every 2 weeks (total dose/cycle [bolus and continuous infusion] is 2,800 mg/m2; in combination with leucovorin and irinotecan) until disease progression or unacceptable toxicity (Ref).
mFOLFOX or FOLFOX regimen: IV: 400 mg/m2 bolus on day 1, followed by 2,400 mg/m2 over 46 hours (as a continuous infusion) every 2 weeks (total dose/cycle [bolus and continuous infusion] is 2,800 mg/m2; in combination with leucovorin and oxaliplatin) until disease progression or unacceptable toxicity (Ref).
Unknown primary cancer, squamous cell (off-label use): IV: 750 mg/m2/day continuous infusion for 5 days (total dose/cycle is 3,750 mg/m2) every 21 days (in combination with docetaxel and cisplatin) for 3 cycles (Ref) or 500 mg/m2/day continuous infusion for 5 days (total dose/cycle is 2,500 mg/m2) every 21 days (in combination with paclitaxel and cisplatin) for 3 cycles (Ref) or 400 mg/m2 bolus on day 1 followed by 1,200 mg/m2/day continuous infusion for 2 days (over 46 hours) every 2 weeks (in combination with leucovorin and oxaliplatin) (Ref) or 700 mg/m2/day continuous infusion for 5 days (total dose/cycle is 3,500 mg/m2) (in combination with cisplatin) every 28 days until disease progression or unacceptable toxicity occurs (Ref).
Vulvar cancer, advanced (off-label use): IV: 1,000 mg/m2/day on days 1 to 4 (total dose/cycle is 4,000 mg/m2; in combination with cisplatin and radiation therapy) every 28 days for 2 cycles (Ref) or 750 mg/m2/day continuous infusion days 1 to 5 (total dose/cycle is 3,750 mg/m2) every 14 days for 2 cycles (in combination with concomitant radiation and mitomycin) (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Kenar D. Jhaveri, MD; Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Although only 5% to 20% of fluorouracil is excreted unchanged by the kidney, the intermediate metabolite, alpha-fluoro-beta-alanine (FBAL), accumulates in kidney impairment. FBAL is converted to fluoro mono acetate (FMA), which is associated with neurotoxicity. It has been hypothesized that accumulation of FBAL and FMA may contribute to hyperammonemic encephalopathy reported with the use of fluorouracil (Ref).
Altered kidney function: IV: No dosage adjustment necessary for any degree of kidney impairment (Ref). Note: Monitor patients with advanced kidney disease (eg, eGFR <30 mL/minute/1.73 m2) closely for hyperammonemic encephalopathy (Ref).
Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).
IV: No dosage adjustment necessary (Ref).
Hemodialysis, intermittent (thrice weekly): Fluorouracil (parent drug) is not significantly dialyzable; however, the metabolite, FBAL, may be substantially removed by dialysis (extraction ratio 0.73 to 0.84) (Ref).
IV: No dosage adjustment necessary. When scheduled dose falls on a hemodialysis day, administer after hemodialysis (Ref). Note: Monitor patients closely for the development of hyperammonemic encephalopathy associated with FBAL accumulation in patients with end-stage kidney disease. Removal of FBAL by hemodialysis may be effective in preventing or treating hyperammonemia associated with elevated FBAL concentrations (Ref).
Peritoneal dialysis: IV: Not significantly dialyzable (Ref): No dosage adjustment necessary. Note: Monitor patients closely for hyperammonemic encephalopathy (Ref).
CRRT: IV: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): IV: No dosage adjustment necessary. When scheduled dose falls on a PIRRT day, administer after PIRRT (Ref).
There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. The following adjustments have been suggested:
Mild or moderate impairment (without concomitant renal impairment): No need for dose adjustment is expected (Ref).
Severe impairment: Use is not recommended; avoid use (Ref).
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: Utilize patient's actual body weight for calculation of BSA- or weight-based dosing; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full, weight-based dosing (or previously tolerated dose level) with subsequent cycles only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref).
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 [HFS]); initiate supportive care for symptomatic relief of HFS.
GI toxicity: Grade 3 or 4 diarrhea (administer fluids, electrolyte replacement, and/or antidiarrheal treatments as necessary); 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 with no history of coronary artery disease or myocardial dysfunction)
CNS toxicity: Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances
Hyperammonemic encephalopathy (initiate ammonia-lowering therapy).
Evidence of acute early-onset or unusually severe toxicity indicative of dihydropyrimidine dehydrogenase deficiency: Withhold or permanently discontinue fluorouracil depending on the onset, duration, and severity of toxicity.
Refer to adult dosing.
(For additional information see "Fluorouracil (systemic): Pediatric drug information")
Note: Dose, frequency, number of doses, and/or start date may vary by protocol and treatment phase. Refer to individual protocols.
Hepatoblastoma: Limited data available: Infants, Children, and Adolescents: IV: 600 mg/m2/dose every 3 weeks on day 2 or 3 (in combination with cisplatin, vincristine ± doxorubicin) (Ref)
Nasopharyngeal carcinoma: Limited data available: Children ≥8 years and Adolescents: Continuous IV infusion: 1,000 mg/m2/day for 3 to 5 days every 3 to 4 weeks for 3 to 4 cycles (in combination with other chemotherapy agents)(Ref)
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no pediatric specific dosage adjustments available; refer to protocols. Based on experience in adult patients, extreme caution should be used in patients with renal impairment and dosing adjustment is suggested.
There are no pediatric specific dosage adjustments available; refer to protocols. Based on experience in adult patients, extreme caution should be used in patients with hepatic impairment and dosing adjustment is suggested.
The following adverse drug reactions are derived from product labeling unless otherwise specified.
Postmarketing:
Cardiovascular: Acute myocardial infarction (Steger 2012), angina pectoris (Steger 2012), cardiac arrhythmia (Steger 2012), cardiotoxicity (including takotsubo syndrome) (McGlinchey 2001; Steen 2023), chest pain (Pottage 1978), coronary artery vasospasm (Connolly 2010), heart failure (Fakhri 2016), ischemic heart disease (Steger 2012), pericarditis (Killu 2011), thrombophlebitis, vein discoloration, ventricular fibrillation (Fradley 2013)
Dermatologic: Changes in nails (including nail loss), palmar-plantar erythrodysesthesia, skin fissure, skin photosensitivity, xeroderma
Gastrointestinal: Diarrhea, dysgeusia (Syed 2016), esophagopharyngitis, gastrointestinal ulcer, nausea, stomatitis, vomiting
Hematologic & oncologic: Neutropenia, pancytopenia
Hypersensitivity: Hypersensitivity reaction (including anaphylaxis)
Nervous system: Euphoria, headache, hyperammonemic encephalopathy (Kitai 2016; Nishikawa 2017), leukoencephalopathy (Hemachudha 2023), neurological abnormality (including ataxia, cerebellar syndrome [acute], confusion, disorientation)
Ophthalmic: Lacrimal stenosis, lacrimation, nystagmus disorder, photophobia, visual disturbance
Respiratory: Epistaxis
There are no contraindications listed in the manufacturer’s US labeling.
Canadian labeling: Known hypersensitivity to fluorouracil or any component of the formulation; debilitated patients; poor nutritional state; depressed bone marrow function following radiotherapy or therapy with other antineoplastic agents; potentially serious infections.
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.
• 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. The risks of resuming fluorouracil in patients with resolved cardiotoxicity have not been established. In a scientific statement from the American Heart Association, 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. 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).
• 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.
• 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. 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. 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 mutations of the dihydropyrimidine dehydrogenase (DPD) gene (DPYD) 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 (according to the prescribing information). The Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group both offer guidance for fluorouracil dosing in patients with known reduced DPD activity (CPIC [Amstutz 2018]; DPWG [Lunenberg 2020]). Consider testing for genetic variants of DPYD prior to fluorouracil initiation to reduce the risk of serious adverse reactions if the patient’s clinical status permits and based on clinical judgement. Serious adverse reactions may still occur even if DPYD variants are not identified.
Concurrent drug therapy issues:
• 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 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intravenous:
Generic: 500 mg/10 mL (10 mL); 1 g/20 mL (20 mL); 2.5 g/50 mL (50 mL); 5 g/100 mL (100 mL)
Solution, Intravenous [preservative free]:
Adrucil: 500 mg/10 mL (10 mL [DSC]); 2.5 g/50 mL (50 mL [DSC]); 5 g/100 mL (100 mL [DSC])
Generic: 500 mg/10 mL (10 mL); 1 g/20 mL (20 mL); 2.5 g/50 mL (50 mL); 5 g/100 mL (100 mL)
Yes
Solution (Fluorouracil Intravenous)
1 g/20 mL (per mL): $0.33 - $1.43
2.5 gm/50 mL (per mL): $0.29 - $0.69
5 g/100 mL (per mL): $0.29 - $0.69
500 mg/10 mL (per mL): $0.33 - $1.59
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Generic: 50 mg/mL (10 mL, 100 mL); 500 mg/10 mL (10 mL); 5 g/100 mL (100 mL)
IV: IV administration rate varies by protocol; refer to specific reference for protocol. May be administered by IV push, IV bolus, or as a continuous infusion. Fluorouracil may be an irritant (Ref); avoid extravasation.
The pharmacy bulk vial is NOT for direct infusion.
When administering bolus fluorouracil, 30 minutes of cryotherapy is recommended to prevent oral mucositis (Ref).
Ophthalmic (off-label route):
Intraoperative topical application: Aseptically apply fluorouracil-saturated sponges to surgical site of glaucoma filtration surgery for 5 minutes (Ref).
Postoperative subconjunctival injections were administered 90 to 180 degrees away from the surgical site (Ref).
IV: Administration rate varies by protocol; refer to specific reference for protocol. May be administered undiluted by IV push, or further diluted in appropriate fluids and administered by IV bolus, or as a continuous infusion. Avoid extravasation (may be an irritant).
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Breast cancer: Management of breast cancer.
Colon and rectal cancer: Management of colon and rectal cancer.
Gastric cancer: Management of stomach (gastric) cancer.
Pancreatic cancer: Management of pancreatic cancer.
Guideline recommendations: American Society of Clinical Oncology:
Potentially curable pancreatic cancer: American Society of Clinical Oncology (ASCO) guidelines (ASCO [Khorana 2019]) recommend fluorouracil as part of the modified FOLFIRINOX regimen (fluorouracil, leucovorin, oxaliplatin, and irinotecan), as the preferred adjuvant therapy in patients without concerns for toxicity or tolerance, and in the absence of medical or surgical contraindications. Alternatively, if there are concerns of toxicity or tolerance, fluorouracil (plus leucovorin calcium) is an option that may be offered.
Locally advanced, unresectable pancreatic cancer: According to the ASCO guidelines for locally advanced, unresectable pancreatic cancer (ASCO [Balaban 2016]), induction with ≥6 months of initial systemic therapy (with a combination regimen) is recommended in patients with an Eastern Cancer Cooperative Group (ECOG) performance status of 0 or 1, a favorable comorbidity profile, a preference for aggressive therapy, and a suitable support system; there is no clear evidence to encourage one regimen over another. If disease progression occurs, treatment according to guidelines for metastatic pancreatic cancer should be offered.
Metastatic pancreatic cancer: ASCO guidelines (ASCO [Sohal 2020]) recommend the FOLFIRINOX regimen (fluorouracil, leucovorin, oxaliplatin, and irinotecan) as first-line therapy in patients with an ECOG performance status of 0 or 1, a favorable comorbidity profile, a preference for aggressive therapy, a suitable support system, and access to a chemotherapy port/infusion pump management service. For patients who received an alternative first-line (gemcitabine-based) therapy and meet the above criteria, preferred second-line therapy includes fluorouracil in combination with irinotecan (liposomal) or conventional irinotecan (if liposomal irinotecan is unavailable), or fluorouracil in combination with oxaliplatin may also be considered. For patients with a performance status of 2 or with comorbidities, fluorouracil (with leucovorin; may add irinotecan [liposomal]) may be considered as an option for second-line therapy (with proactive dose/schedule adjustments to minimize toxicities).
Anal carcinoma; Biliary tract cancer, advanced; Bladder cancer, muscle-invasive; Cervical cancer; Esophageal cancer; Glaucoma surgery, adjunctive therapy; Head and neck cancer, advanced; Neuroendocrine tumors: Pancreatic; Penile cancer, advanced, squamous cell; Small bowel adenocarcinoma, advanced or metastatic; Unknown primary cancer, squamous cell; Vulvar cancer, advanced
Fluorouracil may be confused with floxuridine, flucytosine
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Continuous infusion: 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.
Inhibits CYP2C9 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Allopurinol: May decrease serum concentrations of the active metabolite(s) of Fluorouracil Products. Risk X: Avoid combination
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Amisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapy
Antithymocyte Globulin (Equine): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of cytotoxic chemotherapy is reduced. Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Brivudine: May enhance the adverse/toxic effect of Fluorouracil Products. Risk X: Avoid combination
Chikungunya Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination
Cimetidine: May increase the serum concentration of Fluorouracil Products. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Risk X: Avoid combination
Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
CloZAPine: Fluorouracil Products may enhance the myelosuppressive effect of CloZAPine. CloZAPine may enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing cytotoxic chemotherapy several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
Dabrafenib: Fluorouracil Products may enhance the QTc-prolonging effect of Dabrafenib. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Fexinidazole: Fluorouracil Products may enhance the myelosuppressive effect of Fexinidazole. Fexinidazole may enhance the QTc-prolonging effect of Fluorouracil Products. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Fluorouracil Products: May enhance the QTc-prolonging effect of other Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Folic Acid: May enhance the adverse/toxic effect of Fluorouracil Products. Risk C: Monitor therapy
Fosphenytoin-Phenytoin: CYP2C9 Inhibitors (Weak) may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy
Gemcitabine: May increase the serum concentration of Fluorouracil (Systemic). Risk C: Monitor therapy
Gimeracil: May increase the serum concentration of Fluorouracil Products. Risk X: Avoid combination
Haloperidol: May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating chemotherapy if possible. If vaccination occurs less than 2 weeks prior to or during chemotherapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Interferons (Alfa): May increase the serum concentration of Fluorouracil Products. Risk C: Monitor therapy
Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: Consider therapy modification
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Leucovorin Calcium-Levoleucovorin: May enhance the adverse/toxic effect of Fluorouracil Products. Risk C: Monitor therapy
Levoketoconazole: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Levoketoconazole. Risk X: Avoid combination
Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
MetroNIDAZOLE (Systemic): May increase the serum concentration of Fluorouracil Products. Risk C: Monitor therapy
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Ondansetron: May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification
Pentamidine (Systemic): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Antidepressants (Moderate Risk): Fluorouracil Products may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Antipsychotics (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Kinase Inhibitors (Moderate Risk): Fluorouracil Products may enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Ritlecitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants, such as cytotoxic chemotherapy, prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
TOLBUTamide: CYP2C9 Inhibitors (Weak) may increase the serum concentration of TOLBUTamide. Risk C: Monitor therapy
Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Fluorouracil Products may increase the serum concentration of Vitamin K Antagonists. Management: Monitor INR and for signs/symptoms of bleeding closely when a fluorouracil product is combined with a vitamin K antagonist (eg, warfarin). Anticoagulant dose adjustment will likely be necessary. Risk D: Consider therapy modification
Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Patients who could become pregnant and patients with partners who could become pregnant should use effective contraception during treatment and for 3 months following cessation of fluorouracil therapy.
Based on the mechanism of action and available human data, fluorouracil may cause fetal harm if administered during pregnancy (NTP 2013). Use in the first trimester is not recommended (Silverstein 2020).
The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). In general, if chemotherapy is indicated, it should be avoided during in the first trimester, there should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation (ESMO [Peccatori 2013]).
A long-term observational research study is collecting information about the diagnosis and treatment of cancer during pregnancy. For additional information about the pregnancy and cancer registry or to become a participant, contact Cooper Health (1-877-635-4499).
It is not known if fluorouracil is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made to discontinue breastfeeding or to discontinue fluorouracil, taking into account the importance of treatment to the breastfeeding patient. Other guidance suggests waiting at least 24 hours after the last dose of fluorouracil and feeding with breast milk; however, actual recommendations should be individualized. Patients may maintain milk supply by expressing during treatment; however, milk supply is expected to be decreased by systemic chemotherapy (ABM [Johnson 2020]).
Increase dietary intake of thiamine.
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 (monitor closely in patients receiving concomitant coumarin-derivative anticoagulants). Monitor for signs/symptoms of palmar-plantar erythrodysesthesia syndrome, cardiotoxicity, CNS toxicity, stomatitis, diarrhea, and hyperammonemic encephalopathy. Promptly evaluate any symptoms suggestive of cardiotoxicity. Consider monitoring ECG in patients on concomitant QT prolonging medications.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]). Obtain baseline blood pressure, electrocardiogram, lipid profile, hemoglobin A1c, and assess cardiovascular risk score; obtain a baseline echocardiography (transthoracic preferred) in patients with a history of symptomatic cardiovascular disease (ESC [Lyon 2022]).
Fluorouracil is a pyrimidine analog antimetabolite that interferes with DNA and RNA synthesis; after activation, F-UMP (an active metabolite) is incorporated into RNA to replace uracil and inhibit cell growth; the active metabolite F-dUMP, inhibits thymidylate synthetase, depleting thymidine triphosphate (a necessary component of DNA synthesis).
Distribution: Fluorouracil distributes throughout the body, including brain tissue, CSF, bone marrow, intestinal mucosa, and liver.
Metabolism: Hepatic; via a dehydrogenase enzyme; FU must be metabolized to form active metabolites, 5-fluoroxyuridine monophosphate (F-UMP) and 5-5-fluoro-2’-deoxyuridine-5’-O-monophosphate (F-dUMP)
Half-life elimination: Following bolus infusion: 8 to 20 minutes
Excretion: Urine (5% to 20% as unchanged drug within 6 hours; metabolites over 3 to 4 hours)
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