Fluorouracil (Systemic)

Dosage Forms

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 [DSC]); 5 g/100 mL (100 mL)

Solution, Intravenous [preservative free]:

Adrucil: 500 mg/10 mL (10 mL); 2.5 g/50 mL (50 mL); 5 g/100 mL (100 mL)

Generic: 2.5 g/50 mL (50 mL); 5 g/100 mL (100 mL)

Pharmacology

Mechanism of Action

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).

Pharmacokinetics/Pharmacodynamics

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)

Excretion

Urine (5% to 20% as unchanged drug within 6 hours; metabolites over 3 to 4 hours)

Half-Life Elimination

Following bolus infusion: 8 to 20 minutes

Use: Labeled Indications

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 (ASCO):

Metastatic pancreatic cancer: ASCO guidelines (ASCO [Sohal 2018]) recommend the FOLFIRINOX regimen (fluorouracil, leucovorin, oxaliplatin, and irinotecan) as first-line therapy in patients with Eastern Cancer Cooperative Group (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 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 comorbidities, fluorouracil (with leucovorin) may be considered as an option for second-line therapy.

Potentially curable pancreatic cancer: 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.

Use: Off Label

Anal carcinomaa

Data from a randomized, controlled, multicenter phase III study support the use of continuous infusion fluorouracil (in combination with mitomycin and radiation therapy) for management of anal carcinoma Ajani 2008, Gunderson 2012. Data from another randomized phase III study also support the use of fluorouracil (in combination with mitomycin and radiation therapy) in the treatment of anal cancer Flam 1996.

Bladder cancer (muscle invasive)ayes

Data from a large multicenter phase 3 study support the use of continuous infusion fluorouracil (in combination with systemic mitomycin and radiation therapy) in the management of muscle-invasive bladder cancer James 2012.

Based on the American Urological Association/American Society of Clinical Oncology/American Society for Radiation Oncology/Society of Urologic Oncology guideline for the treatment of nonmetastatic muscle-invasive bladder cancer, fluorouracil in combination with mitomycin and radiation is an option for radiation sensitizing chemotherapy in patients receiving multi-modal bladder conserving therapy for the management of nonmetastatic muscle-invasive bladder cancer.

Cervical cancera

Data from a randomized phase III study support the use of continuous infusion fluorouracil (in combination with cisplatin and radiation therapy) for the management of cervical cancer Eifel 2004, Morris 1999.

Esophageal cancer, advanceda

Data from a large, randomized, phase III trial support the use of fluorouracil in combination with epirubicin and cisplatin (ECF regimen) pre- and postoperatively for the management of adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus Cunningham 2006. Two large phase III trials illustrated that fluorouracil (in combination with cisplatin and docetaxel) is effective in the treatment of gastric and gastroesophageal cancer Ajani 2007, Van Cutsem 2006. Another phase III study supports the use of fluorouracil (in combination with epirubicin and either cisplatin or oxaliplatin) for the management of advanced esophagogastric cancer Sumpter 2005. Data from a randomized phase III trial suggests that fluorouracil (in combination with cisplatin and mitomycin [MCF regimen]) may be an effective regimen in the treatment of advanced esophageal cancer Ross 2002. Additionally, data from a small phase III trial (CALGB 9781) supports the use of fluorouracil (in combination with cisplatin and radiation) as preoperative therapy for esophageal cancer Tepper 2008.

Glaucoma surgery (adjunctive therapy)b

Data (including long-term follow-up outcomes) from a small study comparing topical intraoperative application of fluorouracil to topical mitomycin support the use of fluorouracil during primary trabeculectomy to help reduce scarring Palanca-Capistrano 2009, WuDunn 2002. Clinical experience also suggests the utility of fluorouracil as an adjunctive therapy in glaucoma surgery, either as topical intraoperative application (preferred) or as postoperative subconjunctival injection Cabourne 2015, Green 2014.

Head and neck cancera

Data from multiple phase III randomized studies support the use of fluorouracil (in combination with carboplatin ± radiation) for the treatment of advanced squamous cell head and neck cancer Bourhis 2012, Denis 2004, Forastiere 1992. Fluorouracil (in combination with cetuximab and either cisplatin or carboplatin) for the first-line treatment of recurrent or metastatic squamous cell head and neck cancer is supported by data from a phase III randomized study Vermorken 2008. Data from other large randomized phase III trials support the use of fluorouracil (in combination with docetaxel and cisplatin followed by chemoradiation or radiation alone) for the treatment of unresectable locally advanced head and neck cancer Posner 2007, Vermorken 2007. The combination of fluorouracil and cisplatin for the treatment of advanced head and neck cancer is supported by data from a phase III study Gibson 2005.

Hepatobiliary cancers (advanced)c

Data from a small phase II study supports the use of fluorouracil (in combination with gemcitabine and leucovorin) in the management of unresectable or metastatic biliary tract and gall bladder adenocarcinoma Alberts 2005.

Neuroendocrine tumors (pancreatic)c

Data from a retrospective study support the use of fluorouracil (in combination with doxorubicin and streptozocin) for the treatment of locally advanced or metastatic pancreatic neuroendocrine tumors Kouvaraki 2004.

Penile cancer (advanced) (squamous cell)c

Data from a small retrospective study support the use of fluorouracil (in combination with cisplatin) for the treatment of inoperable locally advanced or metastatic squamous cell penile cancer Di Lorenzo 2012.

Unknown primary cancer (squamous cell)c

Data extrapolated from two randomized phase III studies in squamous cell head and neck cancers (including locally advanced larynx, hypopharynx, pharynx, oropharynx, and oral cavity cancers) suggest that the use of fluorouracil (in combination with cisplatin and either paclitaxel or docetaxel) for the treatment of squamous cell unknown primary cancer may be beneficial Hitt 2005, Pointreau 2009. Fluorouracil (in combination with oxaliplatin and leucovorin [FOLFOX]) may also be an option for the treatment of unknown primary cancer Cheeseman 2002. Data from a retrospective analysis in patients with cancer of unknown primary suggests that fluorouracil in combination with cisplatin may be active in the treatment of this condition Kusaba 2007.

Vulvar cancer, advancedc

Data from a small prospective phase II trial support the use of fluorouracil (in combination with mitomycin and radiation) for the treatment of locally advanced or recurrent vulvar carcinoma Landoni 1996.

Contraindications

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.

Dosage and Administration

Dosing: Adult

Breast cancer: IV:

CEF or FEC regimen: 500 mg/m² on days 1 and 8 every 28 days (in combination with cyclophosphamide and epirubicin) for 6 cycles (Levine 1998).

CMF regimen: 600 mg/m² on days 1 and 8 every 28 days (in combination with cyclophosphamide and methotrexate) for 6 cycles (Goldhirsch 1998; Levine 1998).

CAF or FAC regimen (off-label dosing): 500 mg/m² on days 1 and 8 every 21 to 28 days (in combination with cyclophosphamide and doxorubicin) for 6 cycles (Assikis 2003).

Colorectal cancer: IV: 400 mg/m² bolus on day 1, followed by 1,200 to 1,500 mg/m²/day continuous infusion for 2 days (over 46 hours) every 2 weeks (in combination with leucovorin ± either oxaliplatin or irinotecan) or

Roswell Park regimen: 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 (Haller 2005).

FOLFOX6 and mFOLFOX6 regimen: 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) until disease progression or unacceptable toxicity occurs (Cheeseman 2002).

FOLFIRI regimen: 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 irinotecan) until disease progression or unacceptable toxicity occurs; after 2 cycles, may increase continuous infusion fluorouracil dose to 1,500 mg/m²/day (over 46 hours) (Andre 1999).

FLOX regimen (off-label dosing): 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 (Kuebler 2007).

Gastric cancer: IV: 200 to 1,000 mg/m²/day as a continuous infusion over 24 hours (as part of a platinum-containing regimen); the duration and frequency of each cycle varies based on the dose and regimen.

CF regimen: 1,000 mg/m²/day continuous infusion days 1 to 4 and days 29 to 32 of a 35-day treatment cycle (preoperative chemoradiation; in combination with cisplatin) (Tepper 2008).

ECF regimen (resectable disease): 200 mg/m²/day continuous infusion days 1 to 21 every 3 weeks (in combination with epirubicin and cisplatin) for 6 cycles (3 cycles preoperatively and 3 cycles postoperatively) (Cunningham 2006).

ECF or EOF regimen (advanced disease): 200 mg/m²/day continuous infusion days 1 to 21 every 3 weeks (in combination with epirubicin and either cisplatin or oxaliplatin) for a planned duration of 24 weeks (Sumpter 2005).

TCF or DCF regimen: 750 mg/m²/day continuous infusion days 1 to 5 every 3 weeks (in combination with docetaxel and cisplatin) until disease progression or unacceptable toxicity occurs (Ajani 2007; Van Cutsem 2006).

ToGA regimen (HER2-positive): 800 mg/m²/day continuous infusion days 1 to 5 every 3 weeks (in combination with cisplatin and trastuzumab) until disease progression or unacceptable toxicity occurs (Bang 2010).

Pancreatic cancer: IV:

Metastatic disease: FOLFIRINOX regimen: 400 mg/m² bolus on day 1, followed by 1,200 mg/m²/day continuous infusion for 2 days (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 (Conroy 2011).

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 (ASCO [Khorana 2019]).

mFOLFIRINOX regimen: 2,400 mg/m² as a continuous infusion over 46 hours every 14 days (in combination with leucovorin, irinotecan, and oxaliplatin) for 24 weeks (Conroy 2018). According to ASCO guidelines, mFOLFIRINOX is the preferred first-line adjuvant regimen for potentially curable disease (ASCO [Khorana 2019]).

Fluorouracil with leucovorin (off-label dosing): 425 mg/m²/day (bolus) days 1 to 5 every 28 days (in combination with leucovorin) for 6 cycles (Neoptolemos 2004; Neoptolemos 2010). According to ASCO guidelines for potentially curable pancreatic cancer, fluorouracil with leucovorin may be considered as an alternative therapy if toxicity/tolerance is a concern (ASCO [Khorana 2019]).

Chemoradiation therapy (off-label dosing): 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 (Regine 2008). 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 (ASCO [Khorana 2019]).

Anal carcinoma (off-label use): IV: 1,000 mg/m²/day continuous infusion days 1 to 4 and days 29 to 32 (in combination with mitomycin and radiation therapy) (Ajani 2008; Flam 1996)

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 (in combination with mitomycin and radiation therapy) (James 2012).

Cervical cancer (off-label use): IV: 1,000 mg/m²/day continuous infusion days 1 to 4 (in combination with cisplatin and radiation therapy) every 3 weeks for 3 cycles (Eifel 2004; Morris 1999).

Esophageal cancer (off-label use): IV:

CF regimen: 1,000 mg/m²/day continuous infusion days 1 to 4 and days 29 to 32 of a 35-day treatment cycle (preoperative chemoradiation; in combination with cisplatin) (Tepper 2008).

ECF regimen (resectable disease): 200 mg/m²/day continuous infusion days 1 to 21 every 3 weeks (in combination with epirubicin and cisplatin) for 6 cycles (3 cycles preoperatively and 3 cycles postoperatively) (Cunningham 2006).

ECF or EOF regimen (advanced disease): 200 mg/m²/day continuous infusion days 1 to 21 every 3 weeks (in combination with epirubicin and either cisplatin or oxaliplatin) for a planned duration of 24 weeks (Sumpter 2005).

MCF regimen: 300 mg/m²/day continuous infusion for up to 6 months (in combination with mitomycin and cisplatin) (Ross 2002).

TCF or DCF regimen: 750 mg/m²/day continuous infusion days 1 to 5 every 3 weeks (in combination with docetaxel and cisplatin) until disease progression or unacceptable toxicity occurs (Ajani 2007; Van Cutsem 2006).

Glaucoma surgery, adjunctive therapy (off-label use): Ophthalmic:

Intraoperative topical application: Apply sponge soaked in fluorouracil 50 mg/mL for 5 minutes (Cabourne 2015; Palanca-Capistrano 2009; WuDunn 2002). Additional data may be necessary to further define the role of fluorouracil in glaucoma surgery.

Postoperative subconjunctival injection: 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 (Cabourne 2015). Additional data may be necessary to further define the role of fluorouracil in glaucoma surgery.

Head and neck cancer, squamous cell (off-label use): IV:

Platinum-Fluorouracil (CF) regimen: 1,000 mg/m²/day continuous infusion days 1 to 4 every 3 weeks (in combination with cisplatin) for at least 6 cycles (Gibson 2005) or 1,000 mg/m²/day continuous infusion days 1 to 4 every 4 weeks (in combination with carboplatin) (Forastiere 1992) or 600 mg/m²/day continuous infusion days 1 to 4, 22 to 25, and 43 to 46 (in combination with carboplatin and radiation) (Bourhis 2012; Denis 2004).

TPF regimen: 1,000 mg/m²/day continuous infusion days 1 to 4 every 3 weeks (in combination with docetaxel and cisplatin) for 3 cycles, and followed by chemoradiotherapy (Posner 2007) or 750 mg/m²/day continuous infusion days 1 to 5 every 3 weeks (in combination with docetaxel and cisplatin) for up to 4 cycles, followed by radiation in patients without progressive disease (Vermorken 2007).

Platinum, 5-FU, and cetuximab regimen: 1,000 mg/m²/day continuous infusion days 1 to 4 every 3 weeks (in combination with cetuximab and either cisplatin or carboplatin) for a total of up to 6 cycles (Vermorken 2008).

Hepatobiliary cancer (off-label use): IV: 600 mg/m² (bolus) on days 1, 8, and 15 every 4 weeks (in combination with gemcitabine and leucovorin) (Alberts 2005). Additional data may be needed to further define the role of fluorouracil in this condition.

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 (Kouvaraki 2004). Additional data may be necessary to further define the role of fluorouracil in the management of this condition.

Penile cancer, advanced, squamous cell (off-label use): IV: 800 to 1,000 mg/m²/day continuous infusion for 4 days every 21 days (in combination with cisplatin) (Di Lorenzo 2012). Additional data may be needed to further define the role of fluorouracil in this condition.

Unknown primary cancer, squamous cell (off-label use): IV: 750 mg/m²/day continuous infusion for 5 days every 21 days (in combination with docetaxel and cisplatin) for 3 cycles (Pointreau 2009) or 500 mg/m²/day continuous infusion for 5 days every 21 days (in combination with paclitaxel and cisplatin) for 3 cycles (Hitt 2005) 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) (Cheeseman 2002) or 700 mg/m²/day continuous infusion for 5 days (in combination with cisplatin) every 28 days until disease progression or unacceptable toxicity occurs (Kusaba 2007). Additional data may be needed to further define the role of fluorouracil in this condition.

Vulvar cancer, advanced (off-label use): IV: 750 mg/m²/day continuous infusion days 1 to 5 every 14 days for 2 cycles (in combination with concomitant radiation and mitomycin) (Landoni 1996). Additional data may be needed to further define the role of fluorouracil in this condition.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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) (Douglass 1993; Ortega 2000; Watanabe 2013)

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) (Buehrlen 2012; Casanova 2012; Mertens 2005; Rodriguez-Galindo 2005)

Dosing: Adjustment for Toxicity

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

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

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

Hematologic toxicity: Grade 4 myelosuppression

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

Cardiovascular toxicity: Angina, MI/ischemia, arrhythmia, or heart failure (in patients with no history of coronary artery disease or myocardial dysfunction)

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

Hyperammonemic encephalopathy

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

The 10 mL vial is a single-use vial; the bulk vial may be used to prepare multiple doses if a sterile transfer device is used. May dispense in a syringe or dilute for infusion.

Administration

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 (Pérez Fidalgo 2012); avoid extravasation.

Ophthalmic (off-label route):

Intraoperative topical application: Aseptically apply fluorouracil-saturated sponges to surgical site of glaucoma filtration surgery for 5 minutes (Cabourne 2015; WuDunn 2002).

Postoperative subconjunctival injections were administered 90 to 180 degrees away from the surgical site (Cabourne 2015).

Dietary Considerations

Increase dietary intake of thiamine.

Storage

Store intact vials at 20°C to 25°C (68°F to 77°F). Do not freeze. Protect from light. Pharmacy bulk vials should be used within 4 hours of initial entry. Syringes and solutions diluted for infusion may be stored for up to 4 hours (at room temperature) prior to administration (according to the manufacturer). Fluorouracil 50 mg/mL in NS was stable in polypropylene infusion pump syringes for 7 days when stored at 30°C (86°F) (Stiles 1996). Stability of fluorouracil 1 mg/mL or 10 mg/mL in NS or D5W in PVC bags was demonstrated for up to 14 days at 4°C (39.2°F) and 21°C (69.8°F) (Martel 1996). Stability of undiluted fluorouracil (50 mg/mL) in ethylene-vinyl acetate ambulatory pump reservoirs was demonstrated for 3 days at 4°C (39.2°F) (precipitate formed after 3 days) and for 14 days at 33°C (91.4°F) (Martel 1996). Stability of undiluted fluorouracil (50 mg/mL) in PVC ambulatory pump reservoirs was demonstrated for 5 days at 4°C (39.2°F) (precipitate formed after 5 days) and for 14 days at 33°C (91.4°F) (Martel 1996). Follow USP 797 recommendations for beyond use dates based on the level of risk for preparation.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cimetidine: May increase the serum concentration of Fluorouracil Products. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. 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. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Folic Acid: May enhance the adverse/toxic effect of Fluorouracil Products. Monitor therapy

Fosphenytoin-Phenytoin: Fluorouracil Products may increase the serum concentration of Fosphenytoin-Phenytoin. Monitor therapy

Gemcitabine: May increase the serum concentration of Fluorouracil (Systemic). Monitor therapy

Gimeracil: May increase the serum concentration of Fluorouracil Products. Avoid combination

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. 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. Consider therapy modification

Leucovorin Calcium-Levoleucovorin: May enhance the adverse/toxic effect of Fluorouracil Products. Monitor therapy

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. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

MetroNIDAZOLE (Systemic): May increase the serum concentration of Fluorouracil Products. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. 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. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest 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. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

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. Consider therapy modification

Adverse Reactions

Frequency not defined. Toxicity depends on duration of treatment and/or rate of administration.

Cardiovascular: Angina pectoris, cardiac arrhythmia, cardiac failure, cerebrovascular accident, ischemic heart disease, local thrombophlebitis, myocardial infarction, vasospasm, ventricular ectopy

Central nervous system: Cerebellar syndrome (acute), confusion, disorientation, euphoria, headache

Dermatologic: Alopecia, changes in nails (including nail loss), dermatitis, hyperpigmentation (supravenous), maculopapular rash (pruritic), palmar-plantar erythrodysesthesia, skin fissure, skin photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, xeroderma

Gastrointestinal: Anorexia, diarrhea, esophagopharyngitis, gastrointestinal hemorrhage, gastrointestinal ulcer, mesenteric ischemia (acute), nausea, stomatitis, tissue sloughing (gastrointestinal), vomiting

Hematologic & oncologic: Agranulocytosis, anemia, leukopenia (nadir: days 9 to 14; recovery by day 30), pancytopenia, thrombocytopenia

Hypersensitivity: Anaphylaxis, hypersensitivity reaction (generalized)

Ophthalmic: Lacrimal stenosis, lacrimation, nystagmus, photophobia, visual disturbance

Respiratory: Epistaxis

<1%, postmarketing, and/or case reports: Dysgeusia (Syed 2016)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Fluorouracil can cause severe and fatal hematologic toxicity (neutropenia, thrombocytopenia, and anemia). The neutrophil nadir usually occurs between 9 to 14 days after administration. Monitor blood counts prior to each treatment cycle, weekly if administered on a weekly or similar schedule, and as clinically indicated. Withhold fluorouracil for grade 4 hematologic toxicity; when blood counts resolve to grade 1 or lower, resume at a reduced dose.
• Cardiotoxicity: Based on postmarketing reports, fluorouracil may cause cardiotoxicity (angina, MI/ischemia, arrhythmia, and heart failure). Risk factors for cardiotoxicity include continuous infusion administration (versus IV bolus) and coronary artery disease. Withhold fluorouracil for cardiotoxicity. The risks of resuming fluorouracil in patients with resolved cardiotoxicity have not been established. In a scientific statement from the AHA, fluorouracil has been determined to be an agent that may either cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate/major) (AHA [Page 2016]).
• GI toxicity: Fluorouracil is associated with severe diarrhea. Withhold treatment for grade 3 or 4 diarrhea until resolved or to grade 1 or lower, then resume fluorouracil at a reduced dose. Administer fluids, electrolyte replacement, and/or antidiarrheal treatments as necessary. Mucositis, stomatitis, or esophagopharyngitis (which may lead to mucosal sloughing or ulceration) may occur with fluorouracil. The incidence of mucositis is reported to be higher with IV bolus fluorouracil administration (vs continuous infusion). Withhold fluorouracil grade 3 or 4 mucositis; resume at a reduced dose once mucositis has resolved to grade 1 or lower.
• Hand-foot syndrome: Fluorouracil is associated with palmar-plantar erythrodysesthesia (hand-foot syndrome; HFS). Symptoms of HFS include a tingling sensation, pain, swelling, erythema with tenderness, and desquamation. HFS occurs more commonly when fluorouracil is administered as a continuous infusion (compared to IV bolus) and has been reported to occur more frequently in patients with prior chemotherapy exposure. The onset of HFS is usually after 8 to 9 weeks of fluorouracil, although may occur earlier. Initiate supportive care for symptomatic relief of HFS. Withhold fluorouracil for grade 2 or 3 HFS; resume at a reduced dose when HFS has resolved to grade 1 or lower.
• Hyperammonemic encephalopathy: Fluorouracil may result in hyperammonemic encephalopathy in the absence of liver disease or other identifiable cause (postmarketing reports). The onset of hyperammonemic encephalopathy signs/symptoms (altered mental status, confusion, disorientation, coma, or ataxia, in the presence of concomitant elevated serum ammonia level) was within 72 hours after fluorouracil infusion initiation. Withhold fluorouracil for hyperammonemic encephalopathy and initiate ammonia-lowering therapy. The risks of resuming fluorouracil in patients with resolved hyperammonemic encephalopathy have not been established.
• Neurotoxicity: Fluorouracil may cause neurologic toxicity, including acute cerebellar syndrome and other neurologic events (postmarketing reports). Neurologic symptoms included confusion, disorientation, ataxia, or visual disturbances. Withhold fluorouracil for neurologic toxicity. There are insufficient data on the risks of resuming fluorouracil in patients with resolved neurologic toxicity.

Disease-related concerns:

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

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Warfarin: Clinically significant coagulation parameter elevations have been reported with concomitant use of warfarin and fluorouracil. Closely monitor INR and prothrombin time in patients receiving concomitant coumarin-derivative anticoagulants such as warfarin and adjust the anticoagulant dose accordingly.

Other warnings/precautions:

• Administration safety issues: Serious errors have occurred when doses administered by continuous ambulatory infusion pumps have inadvertently been given over 1 to 4 hours instead of the intended extended continuous infusion duration. Depending on protocol, infusion duration may range from 46 hours to 7 days for fluorouracil continuous infusions. Ambulatory pumps utilized for continuous infusions should have safeguards to allow for detection of programming errors. If using an elastomeric device for ambulatory continuous infusion, carefully select the device and double check the flow rate. Appropriate prescribing (in single daily doses [not course doses] with instructions to infuse over a specific time period), appropriate training/certification/education of staff involved with dispensing and administration processes, and independent double checks should be utilized throughout dispensing and administration procedures (ISMP [Smetzer 2015]).
• Antidote: Uridine triacetate (formerly called vistonuridine), has been studied in cases of fluorouracil overdose. In a clinical study of 98 patients who received uridine triacetate for fluorouracil toxicity (due to overdose, accidental capecitabine ingestion, or possible DPD deficiency), 96 patients recovered fully (Bamat 2013). Of 17 patients receiving uridine triacetate beginning within 8 to 96 hours after fluorouracil overdose, all patients fully recovered (von Borstel 2009). Refer to Uridine Triacetate monograph.

Monitoring Parameters

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

Pregnancy

Pregnancy Risk Factor

D

Pregnancy Considerations

Based on the mechanism of action, fluorouracil may cause fetal harm if administered during pregnancy.

Chemotherapy, if indicated, may be administered to pregnant women with breast cancer as part of a combination chemotherapy regimen (common regimens administered during pregnancy include doxorubicin [or epirubicin], cyclophosphamide, and fluorouracil); chemotherapy should not be administered during the first trimester, after 35 weeks' gestation, or within 3 weeks of planned delivery (Amant 2010; Loibl 2006). 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 (Peccatori 2013).

Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during treatment and for 3 months following cessation of fluorouracil therapy.

Patient Education

What is this drug used for?

• It is used to treat colorectal cancer.
• It is used to treat breast cancer.
• It is used to treat stomach cancer.
• It is used to treat pancreatic cancer.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Lack of appetite
• Dry skin
• Hair loss
• Nail changes

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Chest pain
• Shortness of breath
• Excessive weight gain
• Swelling in the arms or legs
• Abnormal heartbeat
• Dizziness
• Passing out
• Severe abdominal pain
• Severe nausea
• Vomiting
• Severe diarrhea
• Swelling of hands or feet
• Change in balance
• Severe fatigue
• Confusion
• Severe mouth irritation
• Burning or numbness feeling
• Involuntary eye movements
• Headache
• Mouth sores
• Sensitivity to lights
• Severe loss of strength and energy
• Vision changes
• Severe injection site pain, burning, edema, or redness
• Redness or irritation of palms or soles of feet
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.