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Fluorouracil (Systemic)

Pronunciation

Pronunciation

(flure oh YOOR a sil)

Index Terms

  • 5-Fluorouracil
  • 5-Fluracil
  • 5-FU
  • 5FU
  • Fluoro Uracil
  • Fluouracil
  • FU

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

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

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

Brand Names: U.S.

  • Adrucil

Pharmacologic Category

  • Antineoplastic Agent, Antimetabolite
  • Antineoplastic Agent, Antimetabolite (Pyrimidine Analog)

Pharmacology

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

Penetrates extracellular fluid, CSF, and third space fluids (eg, pleural effusions and ascitic fluid), marrow, intestinal mucosa, liver and other tissues

Metabolism

Hepatic (90%); 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

Primarily metabolized in the liver; excreted in lung (as expired CO2) and urine (7% to 20% as unchanged drug within 6 hours; also as metabolites within 9 to 10 hours)

Half-Life Elimination

16 minutes (range: 8 to 20 minutes); two metabolites, F-dUMP and F-UMP, have prolonged half-lives depending on the type of tissue

Use: Labeled Indications

Breast cancer: Management of breast cancer

Colon cancer: Management of colon cancer

Gastric cancer: Management of stomach (gastric) cancer

Pancreatic cancer: Management of pancreatic cancer

Rectal cancer: Management of rectal cancer

Use: Unlabeled

Treatment of anal cancer, bladder cancer, cervical cancer, esophageal cancer, head and neck cancer, hepatobiliary cancers, neuroendocrine tumors, penile cancer (metastatic), thymic cancers, and unknown primary cancer

Contraindications

Hypersensitivity to fluorouracil or any component of the formulation; poor nutritional states; depressed bone marrow function; potentially serious infections

Dosing: Adult

Breast cancer (off-label dosing): 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: 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 (off-label dosing): IV:

FLOX regimen: 500 mg/m2 bolus on days 1, 8, 15, 22, 29, and 36 (1 hour after leucovorin) every 8 weeks (in combination with leucovorin and oxaliplatin) for 3 cycles (Kuebler 2007)

FOLFOX6 and mFOLFOX6 regimen: 400 mg/m2 bolus on day 1, followed by 1200 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 (Cheeseman 2002)

FOLFIRI regimen: 400 mg/m2 bolus on day 1, followed by 1200 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; after 2 cycles, may increase continuous infusion fluorouracil dose to 1500 mg/m2/day (over 46 hours) (Andre 1999)

Roswell Park regimen: 500 mg/m2 (bolus) on days 1, 8, 15, 22, 29, and 36 (1 hour after leucovorin) every 8 weeks (in combination with leucovorin) for 4 cycles (Haller 2005)

Gastric cancer (off-label dosing): 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)

TCF or DCF regimen: 750 mg/m2/day continuous infusion days 1 to 5 every 3 weeks or 1000 mg/m2/day continuous infusion days 1 to 5 every 4 weeks (in combination with docetaxel and cisplatin) until disease progression or unacceptable toxicity (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 (Bang 2010)

Pancreatic cancer (off-label dosing): IV:

Chemoradiation therapy: 250 mg/m2/day continuous infusion for 3 weeks prior to and then throughout radiation therapy (Regine 2008)

Fluorouracil-Leucovorin: 425 mg/m2/day (bolus) days 1 to 5 every 28 days (in combination with leucovorin) for 6 cycles (Neoptolemos 2010)

FOLFIRINOX regimen: 400 mg/m2 bolus on day 1, followed by 1200 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 for a recommended 12 cycles (Conroy 2011)

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 (off-label use): IV: 500 mg/m2/day continuous infusion days 1 to 5 and days 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 to 4 weeks (in combination with docetaxel and cisplatin) until disease progression or unacceptable toxicity (Ajani 2007; Van Cutsem 2006)

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) for at least 6 cycles (Forastiere 1992) or 600 mg/m2/day continuous infusion days 1 to4, 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 (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/day (bolus) 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 (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

Nasopharyngeal carcinoma (off-label use): Children ≥8 years and Adolescents: IV: 1,000 mg/m2/day continuous infusion for 3 or 5 days every 3 or 4 weeks (in combination with cisplatin with or without either methotrexate or leucovorin, followed by radiation therapy [± interferon beta]) for 3 or 4 cycles (Buehrlen 2012; Casanova 2012; Mertens 2005; Rodriguez-Galindo 2005). Additional data may be needed to further define the role of fluorouracil in this condition.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; however, extreme caution should be used in patients with renal impairment. The following adjustments have been recommended:

CrCl <50 mL/minute and continuous renal replacement therapy (CRRT): No dosage adjustment necessary (Aronoff 2007).

Hemodialysis:

Administer standard dose following hemodialysis on dialysis days (Janus 2010).

Administer 50% of standard dose following hemodialysis (Aronoff 2007).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; however, extreme caution should be used in patients with hepatic impairment. The following adjustments have been recommended:

Floyd 2006: Bilirubin >5 mg/dL: Avoid use.

Koren 1992: Hepatic impairment (degree not specified): Administer <50% of dose, then increase if toxicity does not occur.

Dosing: Adjustment for Toxicity

According to the manufacturer, treatment should be discontinued for the following: Stomatitis or esophagopharyngitis, leukopenia (WBC <3500/mm3), rapidly falling white blood cell count, intractable vomiting, diarrhea, frequent bowel movements, watery stools, gastrointestinal ulcer or bleeding, thrombocytopenia (platelets <100,000/mm3), hemorrhage

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

May dispense in a syringe or dilute in 50 to 1,000 mL NS or D5W for infusion.

Administration

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. Avoid extravasation (may be an irritant).

Dietary Considerations

Increase dietary intake of thiamine.

Compatibility

See Trissel’s IV Compatibility Database

Storage

Store intact vials at room temperature. Do not refrigerate or freeze. Protect from light. Slight discoloration may occur during storage; does not usually denote decomposition. If exposed to cold, a precipitate may form; gentle heating to 60°C (140°F) will dissolve the precipitate without impairing the potency. According to the manufacturer, pharmacy bulk vials should be used within 4 hours of initial entry. Solutions for infusion in D5LR, D5W, or NS should be used promptly. 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

Alitretinoin (Systemic): CYP2C9 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP2C9 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP2C9 inhibitor. 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

Bosentan: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Cannabis: May increase the serum concentration of CYP2C9 Inhibitors (Strong). More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Carvedilol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

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

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

CYP2C9 Substrates: CYP2C9 Inhibitors (Strong) may decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

Diclofenac (Systemic): CYP2C9 Inhibitors (Strong) may increase the serum concentration of Diclofenac (Systemic). Management: Consider using a lower dose of diclofenac when used together with a strong CYP2C9 inhibitor. Arthrotec (diclofenac and misoprostol) labeling specifically recommends limiting the total daily dose to a maximum of 50 mg twice/day. Consider therapy modification

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

Dronabinol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Dronabinol. Monitor therapy

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

Fosphenytoin: Fluorouracil (Systemic) may increase the serum concentration of Fosphenytoin. Consider therapy modification

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

Gimeracil: May increase the serum concentration of Fluorouracil (Systemic). Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Lacosamide: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Lacosamide. 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. Consider therapy modification

Leucovorin Calcium-Levoleucovorin: May enhance the adverse/toxic effect of Fluorouracil (Systemic). This effect is associated with the ability of leucovorin or levoleucovorin to enhance the anticancer effects of fluorouracil. Monitor therapy

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

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. 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

Ospemifene: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Ospemifene. 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

Parecoxib: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy

Phenytoin: Fluorouracil (Systemic) may increase the serum concentration of Phenytoin. Consider therapy modification

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

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

Ramelteon: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy

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

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

SORAfenib: May decrease the serum concentration of Fluorouracil (Systemic). SORAfenib may increase the serum concentration of Fluorouracil (Systemic). 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

Tetrahydrocannabinol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. 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. Avoid combination

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

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. Avoid combination

Vitamin K Antagonists (eg, warfarin): Fluorouracil (Systemic) may increase the serum concentration of Vitamin K Antagonists. 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, vein pigmentation, ventricular ectopy

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

Dermatologic: Alopecia, changes in nails (including nail loss), dermatitis, 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 9-14; recovery by day 30), pancytopenia, thrombocytopenia

Hypersensitivity: Anaphylaxis, hypersensitivity reaction (generalized)

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

Respiratory: Epistaxis

ALERT: U.S. Boxed Warning

Experienced physician:

It is recommended that fluorouracil injection be given only by or under the supervision of a qualified physician who is experienced in cancer chemotherapy and who is well versed in the use of potent antimetabolites. Because of the possibility of severe toxic reactions, it is recommended that patients be hospitalized at least during the initial course of therapy.

These instructions should be thoroughly reviewed before administration of fluorouracil.

Warnings/Precautions

Concerns related to adverse effects:

• Hand-foot syndrome: Palmar-plantar erythrodysesthesia (hand-foot) syndrome has been associated with systemic fluorouracil. Symptoms include a tingling sensation, which may progress to pain (with walking or holding objects), and then to symmetrical swelling and erythema with tenderness; desquamation may occur. This generally resolves over 5 to 7 days with treatment interruption.

• Toxicity: Discontinue if intractable vomiting, diarrhea, precipitous fall in leukocyte or platelet counts, myocardial ischemia, hemorrhage, gastrointestinal ulcer or bleeding, stomatitis, or esophagopharyngitis occur.

Disease-related concerns:

• Dihydropyrimidine dehydrogenase deficiency (DPD): Administration to patients with genetic DPD has been associated with prolonged clearance and increased toxicity (diarrhea, neutropenia, and neurotoxicity) following administration; rechallenge has resulted in recurrent toxicity (despite dose reduction).

• Heart failure: In a scientific statement from the American Heart Association (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]).

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Metastatic disease: Use with caution in patients with widespread metastatic marrow involvement.

• Renal impairment: Use with caution in patients with renal impairment.

Concurrent drug therapy issues:

• Alkylating agents: Use with caution in poor-risk patients who have had previous use of alkylating agents.

• 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.

Special populations:

• Pelvic radiation recipients: Use with caution in poor-risk patients who have had high-dose pelvic radiation.

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.

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician. The manufacturer’s labeling recommends hospitalizing patients during the first treatment course due to the potential for severe toxicity.

Monitoring Parameters

CBC with differential and platelet count, renal function tests, liver function tests, signs of palmar-plantar erythrodysesthesia syndrome, stomatitis, diarrhea, hemorrhage, or gastrointestinal ulcers or bleeding

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse effects (increased resorptions, embryolethality, and teratogenicity) have been observed in animal reproduction studies. Based on the mechanism of action, fluorouracil may cause fetal harm if administered during pregnancy (according to the manufacturer’s labeling).

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).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, dry skin, hair loss, or nail changes. Have patient report immediately to prescriber signs of infection; signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; 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); angina; severe abdominal pain; severe nausea; vomiting; severe diarrhea; swelling of hands or feet; numbness or tingling in hands or feet; confusion; mouth irritation; 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; or redness or irritation of palms or soles of feet (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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