Version July 2025
Dosage guidance:
Clinical considerations: Refer to the protocol or institutional guidance for additional details of off-label dosing.
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 [or cisplatin] and radiation therapy) (Ref).
Advanced, metastatic, or locally unresectable 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).
Modified DCF regimen: IV: 1,200 mg/m2/day continuous infusion on days 1 and 2 (total dose/cycle is 2,400 mg/m2) of a 14-day cycle (in combination with docetaxel and cisplatin) for 8 cycles (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).
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).
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 six phase 3 studies, a favorable 5-year overall survival was demonstrated with 6 months (compared to 3 months) of adjuvant FOLFOX therapy in the subgroup of patients with T4 and/or N2 stage III 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 (in patients without disease progression, nivolumab was administered for a maximum of 2 years) (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).
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).
Pembrolizumab/trastuzumab/cisplatin/fluorouracil (HER2-positive gastroesophageal junction adenocarcinoma): IV: 800 mg/m2/day as a continuous infusion on days 1 to 5 (total dose/cycle is 4,000 mg/m2) every 3 weeks; 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).
Tislelizumab/platinum/fluorouracil regimen (unresectable or metastatic esophageal squamous cell carcinoma): IV: 750 to 800 mg/m2/day as a continuous infusion on days 1 to 5 (total dose/cycle is 3,750 to 4,000 mg/m2) of a 21-day treatment cycle (in combination with cisplatin or oxaliplatin and tislelizumab; may limit platinum to 6 cycles per local guidelines or provider discretion); continue treatment until disease progression or unacceptable toxicity (in patients without disease progression, tislelizumab could be discontinued after 2 years of treatment per provider discretion) (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 (in patients without disease progression, nivolumab was administered for a maximum of 2 years) (Ref).
Pembrolizumab/cisplatin/fluorouracil (HER2-negative gastric or gastroesophageal junction cancer): IV: 800 mg/m2/day as a continuous infusion on days 1 to 5 (total dose/cycle is 4,000 mg/m2) every 3 weeks; continue pembrolizumab and fluorouracil until disease progression or unacceptable toxicity or (in patients without disease progression) for up to 24 months (Ref).
Pembrolizumab/trastuzumab/cisplatin/fluorouracil (HER2-positive gastric adenocarcinoma): IV: 800 mg/m2/day as a continuous infusion on days 1 to 5 (total dose/cycle is 4,000 mg/m2) every 3 weeks; 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).
Tislelizumab/cisplatin/fluorouracil (HER2-negative, gastric or gastroesophageal junction cancer): IV: 800 mg/m2/day as a continuous infusion on days 1 to 5 (total dose/cycle is 4,000 mg/m2) of a 21-day treatment cycle (in combination with tislelizumab and cisplatin for up to 6 cycles); continue tislelizumab until disease progression or unacceptable toxicity (in patients without disease progression, tislelizumab could be discontinued after 2 years of treatment per provider discretion) (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).
Zolbetuximab/mFOLFOX regimen (claudin 18.2 positive, HER2-negative, gastric or gastroesophageal junction cancer): IV: 400 mg/m2 bolus on day 1, followed by 2,400 mg/m2 over 46 to 48 hours (as a continuous infusion) on days 1, 15, and 29 of a 42- treatment cycle (total dose every 2 weeks [bolus and continuous infusion] is 2,800 mg/m2; in combination with leucovorin, oxaliplatin, and zolbetuximab for 4 cycles); continue zolbetuximab ± optional fluorouracil/leucovorin maintenance until disease progression or unacceptable toxicity (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 (off-label use):
Advanced disease, squamous cell :
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).
Nasopharyngeal carcinoma, locally advanced:
Induction chemotherapy: IV: 600 mg/m2/day continuous infusion on days 1 to 5 (total dose/cycle is 3,000 mg/m2) every 3 weeks (in combination with docetaxel and cisplatin) for 3 induction cycles, followed by concurrent chemoradiotherapy (Ref) or 800 mg/m2 continuous infusion on days 1 to 5 (total dose/cycle is 4,000 mg/m2) every 3 weeks (in combination with cisplatin) for 2 cycles, followed by concurrent chemoradiotherapy (Ref). A minimum of 2 induction cycles are recommended (Ref).
Adjuvant therapy: IV: 800 mg/m2/day continuous infusion on days 1 to 5 (total dose/cycle is 4,000 mg/m2) every 4 weeks (in combination with cisplatin) for 3 cycles (Ref) or 1,000 mg/m2 over 6 to 8 hours on days 1 to 4 (total dose/cycle is 4,000 mg/m2) every 4 weeks (in combination with cisplatin) for 3 cycles (Ref) or 1,000 mg/m2/day continuous infusion on days 1 to 4 (total dose/cycle is 4,000 mg/m2) every 4 weeks (in combination with cisplatin) for 3 cycles (Ref) or 1,000 mg/m2/day continuous infusion on days 1 to 4 (total dose/cycle is 4,000 mg/m2) every 4 weeks (in combination with carboplatin) for 3 cycles starting 4 weeks after completion of radiation therapy (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).
NALIRIFOX regimen (first-line therapy): IV: 2,400 mg/m2 (as a continuous infusion) over 46 hours once every 2 weeks (in combination with irinotecan [liposomal], oxaliplatin, and leucovorin); continue 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).
Note: Other concomitant anticancer therapies may also require treatment interruption, dosage reduction, and/or discontinuation.
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")
Dosage guidance:
Dosing: Dose, frequency, number of doses, and/or start date may vary by protocol and treatment phase. Refer to individual protocols.
Fibrolamellar carcinoma: Limited data available: Triple therapy regimen: Adolescents: Continuous IV infusion: 200 mg/m2/day for 7 days every 14 or 21 days for at least 6 cycles in combination with interferon (or pegylated interferon) and nivolumab (Ref).
Hepatoblastoma: Limited data available: C5V regimen: Infants, Children, and Adolescents: IV: 600 mg/m2/dose every 3 weeks on day 2 or 3; generally used in combination with cisplatin, vincristine (Ref).
Nasopharyngeal carcinoma: Limited data available: Children ≥3 years and Adolescents: Continuous IV infusion: 1,000 mg/m2/day for 4 or 5 days every 3 weeks for 3 cycles in combination with cisplatin (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosage adjustment for toxicity: Specific recommendations for pediatric patients are limited; refer to specific protocol for management in pediatric patients if available, particularly for myelosuppression, cardiotoxicity, dermatologic toxicity (eg, palmar-plantar erythrodysesthesia [hand-foot syndrome]), or GI toxicity (eg, mucositis or diarrhea).
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 kidney 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 liver impairment and dosing adjustment is suggested.
Fluorouracil impairs DNA and RNA synthesis needed for normal hematopoiesis, resulting in clinical anemia, leukopenia, neutropenia, and thrombocytopenia; severe and fatal cases have occurred. Bone marrow suppression is a potential dose-limiting toxicity that is more common with bolus administration than with an extended infusional schedule (Ref). Leukopenia and neutropenia were the most common hematologic toxicities observed in early clinical trials with bolus administration, which has largely fallen out of favor (Ref). Patients with reduced activity of the dihydropyrimidine dehydrogenase (DPD) enzyme are at increased risk of severe bone marrow suppression (particularly neutropenia), develop cytopenias more rapidly, and count recovery may be significantly prolonged due to an inability to eliminate fluorouracil from the body (Ref).
Mechanism: Dose-related; inhibits DNA and RNA synthesis through inhibition of thymidylate synthase and incorporation of fluorinated nucleosides into DNA and RNA (Ref).
Onset: Varied; blood cell counts may be decreased within days of dosing, particularly in patients with reduced DPD activity (Ref). Neutrophil nadirs tend to occur within 9 to 14 days after administration.
Risk factors:
• Bolus administration schedule (Ref)
• Reduced DPD activity (Ref)
• Concurrent chemotherapy (cisplatin, irinotecan, oxaliplatin) (Ref)
• Females (Ref)
• Older age (≥70 years) (Ref)
Cardiotoxicity is a well-known, uncommon, potential adverse reaction of fluorouracil. Angina pectoris is most common; although, acute myocardial infarction, cardiac arrhythmia (clinically significant and asymptomatic ECG changes), heart failure, acute pulmonary edema, pericarditis, and cardiac arrest have all been reported (Ref). Drug interruption and/or treatment of cardiotoxicity may be required; most cases are reversible (Ref).
Mechanism: Not clearly established; though likely multifactorial, the proposed mechanism best supported by the available evidence is coronary vasospasm. Fluorouracil has been shown to induce vasoconstriction of vascular smooth muscle cells in vitro and vasospasm has also been visualized via angiography in vivo (Ref). Other proposed inciting or contributing causes include prothrombotic effects of endothelial injury or direct cellular injury to cardiac myocytes, either from fluorouracil or metabolites such as fluoroacetate (Ref).
Onset: Varied; usually rapid, with most symptoms presenting within 72 hours of administration during the first cycle (Ref). However, cases of delayed presentation of symptoms weeks to months after initiation have also been reported (Ref).
Possible risk factors (data are conflicting):
• Longer duration of infusion (≥3 hours) (Ref)
• Preexisting cardiac disease (Ref)
• Hypertension (Ref)
• Smoking (Ref)
• Concurrent chemotherapy (Ref)
• Prior or concurrent radiation (Ref)
Fluorouracil has been associated with a range of GI toxicities, including diarrhea, mucositis, stomatitis, and esophagopharyngitis. Although GI toxicity is still observed with infusional administration of fluorouracil, it seems to be more common with bolus administration (particularly stomatitis) (Ref).
Mechanism: Not clearly established; likely multifactorial. In the intestine, fluorouracil induces apoptosis of crypt cells leading to decreased mature villous enterocytes and greater volume of fluid passing from small bowel to colon (Ref). Additionally, fluorouracil has been shown to increase lactose intolerance, suggesting an osmotic component to diarrhea for some patients (Ref). Other studies demonstrate activation of nuclear factor (NF)-κB and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species in mucosal cells of humans or animals treated with fluorouracil, leading to increased levels of inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α (Ref).
Onset: Varied; may occur at any point during treatment. Patients with reduced dihydropyrimidine dehydrogenase (DPD) activity treated with fluorouracil often present with rapid onset of severe toxicity (including GI toxicity) after initial fluorouracil treatment (Ref).
Risk factors:
• Bolus administration schedule (Ref)
• Reduced DPD activity (Ref)
• Concurrent use of leucovorin (Ref)
• Concurrent chemotherapy (irinotecan, oxaliplatin) (Ref)
• Females (Ref)
• Older age (≥70 years) (Ref)
• Increased serum bilirubin (Ref)
• Presence of primary colorectal tumor (Ref)
• Resection of primary colorectal tumor (Ref)
• Treatment during summer season (conflicting data) (Ref)
Treatment with fluorouracil, particularly with continuous infusion, may cause palmar-plantar erythrodysesthesia, also known as hand-foot syndrome. Signs and symptoms present almost exclusively on the palms and soles, and may include tingling sensation, pain, swelling, erythema with tenderness, and desquamation. Hyperpigmentation may also occur and resolves upon drug discontinuation (Ref). Rarely, reversible loss of fingerprints has been associated with the syndrome (Ref). Chronic hand-foot syndrome may lead to thickening of the skin, limiting mobility (Ref).
Mechanism: Unknown; direct cytotoxic effects on coiled sweat glands, which are found with greater density in the palms and soles than elsewhere has been proposed, but rarely empirically demonstrated (Ref). An immune-type reaction has also been proposed (Ref). A contributing factor for fluoropyrimidine-associated hand-foot syndrome is that thymidine phosphorylase, which catalyzes the initial step in the anabolic metabolism of fluorouracil, is found in higher concentrations in the palms than other skin (Ref). Theoretically, patients with reduced dihydropyrimidine dehydrogenase enzyme activity may experience reduced fluorouracil clearance and greater toxicity, but a large increase in risk of hand-foot syndrome is not observed in practice (Ref).
Onset: Delayed; typically occurs after 8 to 9 weeks of therapy, although may occur earlier.
Risk factors:
• Infusional administration schedule (Ref)
• Concurrent use of leucovorin (Ref)
• Females (Ref)
• Older age (≥70 years) (Ref)
• Prior chemotherapy exposure
Hyperammonemic encephalopathy has been reported with fluorouracil in the absence of concurrent liver disease. Symptoms have been observed in the setting of markedly elevated serum ammonia and have included altered mental status, ataxia, coma, confusion, and disorientation (Ref).
Mechanism: Not clearly established; catabolism of fluorouracil directly produces ammonium and fluoroacetate, which can inhibit the urea cycle and lead to further increases in serum ammonia (Ref). However, encephalopathy does not occur in the absence of contributing factors such as infection, constipation, and kidney impairment (Ref). Furthermore, the pathophysiology leading to CNS changes secondary to hyperammonemia is also poorly understood. It has been suggested that accumulation of intracellular glutamine, which the primary product from ammonia in the brain, leads to increased intracranial pressure and cerebral edema (Ref). Most reported cases have occurred in Asian patients, but it is unclear if true regional or genetic differences contribute to this toxicity (Ref).
Onset: Varied; case reports primarily describe a rapid onset of symptoms within days of the precipitating dose, although in many cases the precipitating dose was not the first dose administered (Ref).
Risk factors:
• Concurrent infection (Ref)
• Dehydration (Ref)
• Kidney impairment (Ref)
• Constipation (Ref)
• Muscle loss (Ref)
• Concurrent chemotherapy (cisplatin, oxaliplatin) (Ref)
• Hepatic impairment (Ref)
• Higher doses (≥1,800 mg/m2/day) (Ref)
Neurotoxicity has been reported with fluorouracil. Although all neurotoxicity adverse reactions that have been reported are rare, the most described is acute cerebellar syndrome (Ref). Reported symptoms include ataxia, confusion, disorientation, and visual disturbance (including optic neuropathy and vision loss) (Ref). Other neurologic toxicities associated with fluorouracil include cerebrovascular disorders, eye movement disorders, focal dystonia, leukoencephalopathy, parkinsonism, peripheral neuropathy, and seizures (Ref). Patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at increased risk for neurotoxicity and commonly present with additional toxicities (eg, cardiac, gastrointestinal, or hematologic) (Ref).
Mechanism: Not clearly established; may cause dose-dependent direct cellular toxicity within the CNS, particularly the cerebellum. The theory is supported by pathologic examination and that some patients have been successfully rechallenged with fluorouracil without recurrence of neurotoxicity or with less severe symptoms using lower doses than the original inciting treatment (Ref). Neurotoxicity with or without hyperammonemia is commonly reported in patients later found to have reduced DPD activity and therefore greater exposure to fluorouracil due to reduced clearance (Ref). Other reports of central demyelination and leukoencephalopathy suggest an inflammatory mechanism (Ref).
Onset: Varied; case reports describe an acute onset of symptoms, but often weeks to months after initiation of treatment (Ref). Patients with reduced DPD enzyme activity may present with more rapid onset of symptoms relative to initiation of treatment and/or a more protracted course (Ref).
Risk factors:
• Higher doses (>2,200 mg/m2/week or ≥10 mg/kg/week) (Ref)
• Reduced DPD activity (Ref)
Up to 50% of patients may experience excessive tearing (epiphora) with fluorouracil treatment (Ref). Less commonly reported ocular toxicities include lacrimal stenosis, which may require stenting or surgery, eyelid dermatitis, and inflammation of the lid margin (blepharitis), which may result in scarring (cicatricial changes) and ectropion, conjunctival hyperemia, and corneal punctate epithelial erosions (Ref). The less common presentations of ocular toxicity almost always present concurrently with excessive tear formation (Ref). Symptoms typically resolve upon interruption of therapy and application of lubrication with artificial tears, provided fibrosis has not occurred. Referral to an ophthalmologist is recommended for patients whose symptoms do not respond to conservative management and/or have evidence of lacrimal obstruction. Although not specifically reported with fluorouracil, cases of corneal deposits secondary to use of the oral prodrug of fluorouracil (capecitabine) have been reported (Ref).
Mechanism: Not clearly established; appears consistent with a dose- and time-related mechanism. Fluorouracil has been detected in tears and is associated with direct epithelial toxicity at the cornea, conjunctiva, and tear ducts leading to inflammation and dysregulation of healthy tear production (Ref). Over time, this recurrent cellular damage and inflammation leads to stenosis and fibrotic changes (Ref).
Onset: Delayed; case reports typically describe a gradual onset over a period of weeks to months, followed by resolution of symptoms usually within 4 weeks after cessation of therapy, although some symptoms may persist (Ref).
Risk factors:
• Longer duration of therapy (≥12 weeks) (Ref)
• Concurrent anti-cancer therapy (cyclophosphamide, epirubicin, methotrexate, tamoxifen) (Ref)
• Concurrent use of leucovorin (Ref)
• Black patients (Ref)
• Excessive tearing (predictive of development of other ocular toxicities) (Ref)
The following adverse drug reactions are derived from product labeling unless otherwise specified.
Postmarketing:
Cardiovascular: Acute myocardial infarction (Ref), angina pectoris (Ref), cardiac arrhythmia (Ref), cardiotoxicity (including takotsubo syndrome) (Ref), chest pain (Ref), coronary artery vasospasm (Ref), heart failure (Ref), ischemic heart disease (Ref), pericarditis (Ref), thrombophlebitis, vein discoloration, ventricular fibrillation (Ref)
Dermatologic: Changes in nails (including nail loss), palmar-plantar erythrodysesthesia (Ref), skin fissure, skin photosensitivity, xeroderma
Gastrointestinal: Diarrhea (Ref), dysgeusia (Ref), esophagopharyngitis, gastrointestinal ulcer, nausea (Ref), stomatitis (Ref), vomiting
Hematologic & oncologic: Anemia (Ref), leukopenia (Ref), neutropenia (Ref), pancytopenia, thrombocytopenia (Ref)
Hypersensitivity: Hypersensitivity reaction (including anaphylaxis)
Nervous system: Euphoria, headache, hyperammonemic encephalopathy (Ref), leukoencephalopathy (Ref), neurological abnormality (including ataxia, cerebellar syndrome [acute], confusion, disorientation)
Ophthalmic: Blepharitis (Ref), conjunctival hyperemia (Ref), lacrimal stenosis (Ref), lacrimation (Ref), nystagmus disorder, optic neuropathy (Ref), photophobia, vision loss (Ref), 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; available tests may vary in accuracy and design (there are no currently available FDA-approved tests). 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.
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]:
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): $0.22 - $0.69
5 g/100 mL (per mL): $0.22 - $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 2024 [table 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 2023; NIOSH 2024; 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; Head and neck cancer: Nasopharyngeal carcinoma, locally 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
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
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 drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Abrocitinib: May increase immunosuppressive effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid
Allopurinol: May decrease active metabolite exposure of Fluorouracil Products. Risk X: Avoid
Aminolevulinic Acid (Systemic): Photosensitizing Agents may increase photosensitizing effects of Aminolevulinic Acid (Systemic). Risk X: Avoid
Aminolevulinic Acid (Topical): Photosensitizing Agents may increase photosensitizing effects of Aminolevulinic Acid (Topical). Risk C: Monitor
Amisulpride (Oral): May increase QTc-prolonging effects of QT-prolonging Agents (Moderate Risk). Risk C: Monitor
Antithymocyte Globulin (Equine): Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of cytotoxic chemotherapy is reduced. Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor
Antithyroid Agents: Myelosuppressive Agents may increase neutropenic effects of Antithyroid Agents. Risk C: Monitor
Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Baricitinib. Risk X: Avoid
BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of BCG Products. Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Brincidofovir. Risk C: Monitor
Brivudine: May increase adverse/toxic effects of Fluorouracil Products. Risk X: Avoid
Chikungunya Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Chikungunya Vaccine (Live). Risk X: Avoid
Chloramphenicol (Ophthalmic): May increase adverse/toxic effects of Myelosuppressive Agents. Risk C: Monitor
Chloramphenicol (Systemic): Myelosuppressive Agents may increase myelosuppressive effects of Chloramphenicol (Systemic). Risk X: Avoid
Cimetidine: May increase serum concentration of Fluorouracil Products. Risk C: Monitor
Cladribine: Agents that Undergo Intracellular Phosphorylation may decrease therapeutic effects of Cladribine. Risk X: Avoid
Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Cladribine. Risk X: Avoid
CloZAPine: May increase QTc-prolonging effects of Fluorouracil Products. Fluorouracil Products may increase myelosuppressive effects of CloZAPine. 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
Coccidioides immitis Skin Test: Coadministration of Immunosuppressants (Cytotoxic Chemotherapy) and Coccidioides immitis Skin Test may alter diagnostic results. 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 (Inactivated Virus): Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor
COVID-19 Vaccine (mRNA): Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects 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 decrease therapeutic effects of COVID-19 Vaccine (Subunit). Risk C: Monitor
Dabrafenib: Fluorouracil Products may increase QTc-prolonging effects 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
Deferiprone: Myelosuppressive Agents may increase neutropenic effects 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 decrease therapeutic effects of Dengue Tetravalent Vaccine (Live). Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Denosumab: May increase immunosuppressive effects 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 increase immunosuppressive effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid
Domperidone: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Domperidone. Risk X: Avoid
Etrasimod: May increase immunosuppressive effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid
Fexinidazole: Fluorouracil Products may increase myelosuppressive effects of Fexinidazole. Fexinidazole may increase QTc-prolonging effects of Fluorouracil Products. Risk X: Avoid
Filgotinib: May increase immunosuppressive effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid
Fluorouracil Products: May increase QTc-prolonging effects 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
Folic Acid: May increase adverse/toxic effects of Fluorouracil Products. Risk C: Monitor
Fosphenytoin-Phenytoin: CYP2C9 Inhibitors (Weak) may increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Gemcitabine: May increase serum concentration of Fluorouracil (Systemic). Risk C: Monitor
Gimeracil: May increase serum concentration of Fluorouracil Products. Risk X: Avoid
Haloperidol: May increase QTc-prolonging effects 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
Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Inebilizumab. Risk C: Monitor
Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects 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 serum concentration of Fluorouracil Products. Risk C: Monitor
Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects 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 decrease therapeutic effects 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 increase adverse/toxic effects of Fluorouracil Products. Risk C: Monitor
Levoketoconazole: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Levoketoconazole. Risk X: Avoid
Linezolid: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Lipegfilgrastim: Antineoplastic Agents may decrease therapeutic effects 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 increase photosensitizing effects of Methoxsalen (Systemic). Risk C: Monitor
MetroNIDAZOLE (Systemic): May increase serum concentration of Fluorouracil Products. Risk C: Monitor
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Mumps- Rubella- or Varicella-Containing Live Vaccines. Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Nadofaragene Firadenovec: Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid
Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Natalizumab. Risk X: Avoid
Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Ocrelizumab. Risk C: Monitor
Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Ofatumumab. Risk C: Monitor
Olaparib: Myelosuppressive Agents may increase myelosuppressive effects of Olaparib. Risk C: Monitor
Ondansetron: May increase QTc-prolonging effects 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
Palifermin: May increase adverse/toxic effects 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 increase QTc-prolonging effects 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
Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Pidotimod. Risk C: Monitor
Pimecrolimus: May increase immunosuppressive effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid
Pimozide: May increase QTc-prolonging effects of QT-prolonging Agents (Moderate Risk). Risk X: Avoid
Piperacillin: May increase hypokalemic effects of Antineoplastic Agents. Risk C: Monitor
Piperaquine: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Piperaquine. Risk X: Avoid
Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Pneumococcal Vaccines. Risk C: Monitor
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Poliovirus Vaccine (Live/Trivalent/Oral). Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may increase hypersensitivity effects of 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 increase photosensitizing effects of Porfimer. Risk X: Avoid
Promazine: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
QT-prolonging Agents (Highest Risk): May increase QTc-prolonging effects 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 increase QTc-prolonging effects 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
QT-prolonging Antipsychotics (Moderate Risk): May increase QTc-prolonging effects 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
QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May increase QTc-prolonging effects 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
QT-Prolonging Inhalational Anesthetics (Moderate Risk): May increase QTc-prolonging effects 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
QT-prolonging Kinase Inhibitors (Moderate Risk): Fluorouracil Products may increase QTc-prolonging effects 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
QT-prolonging Miscellaneous Agents (Moderate Risk): May increase QTc-prolonging effects 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
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May increase QTc-prolonging effects 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
QT-prolonging Quinolone Antibiotics (Moderate Risk): May increase QTc-prolonging effects 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
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May increase QTc-prolonging effects 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
Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects 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 increase immunosuppressive effects of Ritlecitinib. Risk X: Avoid
Ropeginterferon Alfa-2b: Myelosuppressive Agents may increase myelosuppressive effects 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 increase immunosuppressive effects of Ruxolitinib (Topical). Risk X: Avoid
Sertindole: May increase QTc-prolonging effects of QT-prolonging Agents (Moderate Risk). Risk X: Avoid
Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects 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 Modulators: May increase immunosuppressive effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor
Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Tacrolimus (Topical). Risk X: Avoid
Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects 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
Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Tertomotide. Risk X: Avoid
Thioridazine: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Thioridazine. Risk X: Avoid
Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Tofacitinib. Risk X: Avoid
TOLBUTamide: CYP2C9 Inhibitors (Weak) may increase serum concentration of TOLBUTamide. Risk C: Monitor
Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Typhoid Vaccine. Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Ublituximab: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Ublituximab. Risk C: Monitor
Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Upadacitinib. Risk X: Avoid
Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may decrease therapeutic effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid
Vaccines (Non-Live/Inactivated/Non-Replicating): Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Vaccines (Non-Live/Inactivated/Non-Replicating). Management: Give non-live/inactivated/non-replicating vaccines at least 2 weeks prior to starting chemotherapy when possible. Patients vaccinated less than 14 days before or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider Therapy Modification
Verteporfin: Photosensitizing Agents may increase photosensitizing effects of Verteporfin. Risk C: Monitor
Vitamin K Antagonists: Fluorouracil Products may increase 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 decrease therapeutic effects of Yellow Fever Vaccine. Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Zoster Vaccine (Live/Attenuated): Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Zoster Vaccine (Live/Attenuated). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Zoster Vaccine (Live/Attenuated). Risk X: Avoid
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)
