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Fluorouracil

Pronunciation

Class: Antineoplastic Agents
VA Class: AN300
Chemical Name: 5-fluoro-2,4(1H,3H)-Pyrimidinedione
Molecular Formula: C4H3FN2O2
CAS Number: 51-21-8
Brands: Adrucil

Warning(s)

  • Only for administration by, or under the supervision of, a clinician experienced in cancer chemotherapy and the use of antimetabolites.205 a

  • Severe toxic reactions are possible; hospitalize patients, at least during initial course of therapy.205

Introduction

Pyrimidine antagonist; antimetabolite; antineoplastic agent.205 a

Uses for Fluorouracil

Cancers

Principally for GI, breast, and head and neck cancers.a b

Palliative treatment of carcinoma of the colon, rectum, anus, stomach, biliary tract, esophagus, and pancreas that is not amenable to surgery or irradiation.a b 205

Adjunct to surgery for the treatment of various solid tumors (e.g., adenocarcinoma of the colon,226 227 228 229 230 231 232 233 252 253 256 261 280 rectal carcinoma).230 234 235 236 237 238 239 240 242 243 280

Colorectal Cancer

Drug of choice (combined with leucovorin) as an adjunct to surgery for colorectal cancer.b

Drug of choice (combined with leucovorin and other drugs [e.g., irinotecan, oxaliplatin]) for metastatic colorectal cancer.b

Combination fluorouracil/leucovorin regimens have replaced fluorouracil monotherapy regimens218 266 286 292 294 295 296 300 304 305 as adjuvant therapy for stage III disease.388

Weekly schedule of fluorouracil/leucovorin (high-dose leucovorin or Roswell Park regimen) has equal efficacy as monthly schedule (low-dose or Mayo Clinic schedule), but the weekly schedule is a preferred regimen for adjuvant therapy because of ease of use and less toxicity.386 388 (See Colorectal Cancer under Dosage and Administration.)

Bimonthly, continuous IV infusion schedule of fluorouracil/leucovorin (LV5FU2 or deGramont regimen) also evaluated as adjuvant therapy390 and shown to be safer than direct IV injection regimen of these drugs.388 390 Simplified version of this regimen also evaluated.391 (See Colorectal Cancer under Dosage and Administration.)

Role of regional adjuvant therapy (e.g., portal vein or hepatic artery infusion) for liver metastases requires further elucidation.230 253 256 257 258 259 260 264 275 280

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Leucovorin and levoleucovorin enhance cytotoxicity,221 286 291 303 305 306 307 308 309 310 395 397 potentiate fluorouracil antineoplastic activity, and improve response for palliative advanced colorectal carcinoma treatment;200 201 211 215 216 218 219 220 266 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 311 313 314 315 317 395 designated an orphan drug by FDA for use with leucovorin for metastatic colorectal adenocarcinoma.335

Leucovorin and levoleucovorin may potentiate risk of fluorouracil GI toxicity (e.g., diarrhea, nausea, stomatitis, vomiting) and myelosuppression.214 215 217 218 266 286 289 292 293 294 295 296 311 395

Esophageal Cancer

Drug of choice for treatment of esophageal cancer.b

Has been used alone330 334 336 and in combination therapy (e.g., with cisplatin)b 249 329 330 331 334 336 for the treatment of localized or advanced esophageal cancer.

Gastric Cancer

Drug of choice (with or without leucovorin and/or other drugs [e.g., cisplatin, epirubicin]) for treatment of gastric cancer.b

Anal Cancer

Drug of choice (e.g., combined with mitomycin or cisplatin) for treatment of anal cancer.b

Pancreatic Cancer

Drug of choice as adjunct to surgery and for localized unresectable pancreatic cancer.b

Biliary Tract Cancer

Drug of choice (with or without leucovorin) for treatment of biliary tract cancer.b

Breast Cancer

Drug of choice combined with other drugs (e.g., cyclophosphamide and doxorubicin or methotrexate) as an adjunct to surgery and for metastatic breast cancer.b 244 249 251 279 319 320 322 323 324 325 326 328

Palliative treatment of carcinoma of the breast not amenable to surgery or irradiation.a

Adjunct to surgery, may improve outcome.244 245 246 247 248 249 250 251 254 270 271 272

Has been used most extensively with cyclophosphamide and methotrexate, and is considered a regimen of choice.244 249 251 279 319 320 321 322 323 324 325 326 328

Head and Neck Cancer

Drug of choice combined with cisplatin for head and neck cancer.b

In combination chemotherapy for metastatic or recurrent squamous cell carcinoma of the head and neck.349

Has been used in combination chemotherapy with radiation therapy for palliative treatment of unresectable locally advanced head and neck cancer,337 and for larynx preservation in locally advanced laryngeal or hypopharyngeal cancer.354 355 356 357

Used in combination with docetaxel and cisplatin as induction therapy prior to radiotherapy or chemoradiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck.393 394

Cervical Cancer

Drug of choice combined with other drugs (e.g., cisplatin) for treatment of locally advanced cervical cancer.b

In combination with cisplatin concurrently with radiation therapy for invasive cervical cancer.249 359 360 361 362 364

Metastatic or recurrent cervical cancer.249 365 366 367 369 370 371

Renal Cell Carcinoma

Has been used alone374 or in combination regimens375 376 377 378 379 380 381 382 383 384 for the treatment of metastatic renal cell carcinoma.

Carcinoid Tumors

Drug of choice for treatment of carcinoid tumors.b

Other Uses

Second-line therapy in the treatment of ovarian epithelial cancer, including platinum-refractory disease.b 241 Also, cancers of the liver (e.g., hepatoblastoma).b 249

Fluorouracil Dosage and Administration

Administration

Administer IV.205 a

Has been administered by regional infusion into the venous or arterial blood supply of a tumor (e.g., portal vein or hepatic artery infusions for liver metastases).230 253 256 258 259 264 275 280 a

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

2.5- or 5-g pharmacy bulk package is intended for individual dose preparation, not for direct IV infusion.a

Avoid extravasation.205 a

Dilution

No dilution necessary for usual injection formulation.205 a

Rate of Administration

Administer through a 25-gauge needle at any convenient rate.a

Dosage

Base dosage on actual weight.205 a

Base dosage on estimated lean body mass if patient is obese or has fluid retention.205 a

May calculate dosage based on body surface area.215 218 220 266 275 286 289 292 293 294 295 296 298 300 304 305 317 320 321 322 323 328

Base dosage on clinical and hematologic response and patient tolerance to obtain optimum results with minimum adverse effects.a

Consult published protocols for the dosage and method and sequence of administration of fluorouracil with other chemotherapeutic agents.a

Adults

Usual Dosage
IV

Initially, manufacturers recommend a course of 12 mg/kg once daily for 4 consecutive days, up to 800 mg daily; then (if toxicity does not preclude) administer 6 mg/kg on the 6th, 8th, 10th and 12th days (unless toxicity occurs before then).205 a

Poor risk and inadequate nutrition: initially, manufacturers suggest a course of 6 mg/kg daily for 3 days, up to 400 mg daily; then (if toxicity does not preclude) may administer 3 mg/kg on the 5th, 7th, and 9th days (unless toxicity occurs before then).205 a

Repeat courses: adjust schedule according to reaction to the previous course.205 a

Repeat course at 30-day intervals if toxicity has not been a problem.205 a

Alternatively, when toxicity of initial course has subsided, may administer 10–15 mg/kg (up to 1 g) once weekly for maintenance.205 a

Colorectal Cancer

Various fluorouracil/leucovorin combination dosage regimens have been used.215 220 266 289 296 298 304 305 317

Monthly Schedule (Mayo Clinic Regimen)
Direct IV Injection

Leucovorin 20 mg/m2 IV or levoleucovorin 10 mg/m2 IV followed by fluorouracil 425 mg/m2 IV; administer fluorouracil and either leucovorin or levoleucovorin daily for 5 consecutive days and repeat regimen at 4-week intervals for 2 additional courses; thereafter, may repeat the regimen at intervals of 4–5 weeks provided toxicity from the previous course has resolved completely.286 289 386 388 395 Frequently administered for a total of 6 cycles in the adjuvant setting.386 388

Alternatively, leucovorin 200 mg/m2 IV or levoleucovorin 100 mg/m2 IV over ≥3 minutes followed by fluorouracil 370 mg/m2 IV; administer fluorouracil and either leucovorin or levoleucovorin daily for 5 consecutive days and repeat regimen at 4-week intervals for 2 additional courses; thereafter, may repeat the regimen at intervals of 4–5 weeks provided toxicity from the previous course has resolved completely.286 395 397

Adjust fluorouracil dosage in subsequent courses according to tolerance;286 395 reduce daily fluorouracil dosage by 20% for moderate hematologic or GI toxicity in prior course and by 30% for severe toxicity266 286 289 395 (leucovorin or levoleucovorin dosage is not adjusted286 395 ).

May increase fluorouracil dosage by 10% if no toxicity occurred in the prior course.286 395

Weekly Schedule (Roswell Park Regimen)
IV Infusion

Leucovorin 500 mg/m2 as a 2-hour IV infusion followed by fluorouracil 500 mg/m2 as a slow IV injection administered 1 hour after the start of the leucovorin infusion.386 388 Administer both drugs weekly for 6 consecutive weeks followed by a 2-week rest; repeat cycles every 8 weeks for a total of 4 courses in the adjuvant setting.386 388

Adjust fluorouracil dosage in subsequent courses according to tolerance;286 reduce daily fluorouracil dosage by 20% for moderate hematologic or GI toxicity in prior course and by 30% for severe toxicity266 286 289 (leucovorin dosage is not adjusted286 ).

May increase fluorouracil dosage by 10% if no toxicity occurred in the prior course.286

Bimonthly Schedule (Modified deGramont Regimen)
IV Infusion

Leucovorin 400 mg/m2 as a 2-hour IV infusion on day 1 followed by fluorouracil 400 mg/m2 as an IV injection on day 1; then fluorouracil 1500 mg/m2 as a continuous IV infusion over 23 hours on days 1 and 2 (i.e., total 3000 mg/m2 by continuous IV infusion over 46 hours);391 repeat cycles every 2 weeks.

Breast Cancer

Various combination regimens have been used; consult published protocols for dosages and method and sequence of administration.246 269 271 272 320 321 322 323 324 325 326 328

Avoid arbitrary dose reductions of adjuvant combination chemotherapy; dose intensity appears to be an important factor influencing clinical outcome in early node-positive breast cancer (increasing response with increasing intensity).244 322

Combination Regimen: Cyclophosphamide, Methotrexate, and Fluorouracil
IV

Regimen containing IV fluorouracil in combination with oral cyclophosphamide and IV methotrexate is described in the table.320 321

Drug

Dose

Administration Days per Cycle

Fluorouracil

600 mg/m2 IV (≤60 yrs of age)320 321

Days 1 and 8320 321

Cyclophosphamide

100 mg/m2 orally320 321

Days 1 through 14 320 321

Methotrexate

40 mg/m2 IV (≤60 yrs of age)320 321

Days 1 and 8 320 321

Repeat monthly (i.e., allow a 2-week rest period between cycles).320 321

Total of 6–12 cycles (i.e., 6–12 months of therapy); clinical superiority between 6- versus 12-month regimens not demonstrated.244 319 320 321

Initial fluorouracil and methotrexate dosages have been reduced in patients >60 years of age.321 (See Geriatric Patients under Special Populations.)

Also, dosage was reduced if myelosuppression developed.320 321

Sequential Regimen: Cyclophosphamide, Methotrexate, and Fluorouracil Plus Doxorubicin

In early breast cancer and >3 positive axillary lymph nodes, doxorubicin addition may improve outcome, and sequential regimens (i.e., several courses of doxorubicin first) may be more effective than alternating regimens; no additional benefit when fewer positive nodes are present.323 326

IV

Initially, doxorubicin hydrochloride 75 mg/m2 IV at 3-week intervals for 4 doses.323 328

Subsequently, fluorouracil 600 mg/m2 IV, methotrexate 40 mg/m2 IV, and cyclophosphamide 600 mg/m2 IV at 3-week intervals for 8 cycles.323 328

Total of about 9 months of therapy.323 328

Generally, myelosuppression has delayed cycle rather than reducing dosage.323 328

Prescribing Limits

Adults

General Dosage
IV

Initially (first 4 days), manufacturers recommend maximum of 800 mg daily.205 a

Poor risk and inadequate nutrition: manufacturers recommend initially (first 3 days) maximum of 400 mg daily.205 a

Alternative dosage for maintenance once toxicity of initial course has subsided: manufacturers recommend maximum of 1 g once weekly.205 a

Special Populations

Geriatric Patients

Breast Cancer

In patients >60 years of age receiving oral cyclophosphamide, IV methotrexate, and IV fluorouracil combination therapy, reduce initial methotrexate dosage to 30 mg/m2 and fluorouracil dosage to 400 mg/m2.321

Cautions for Fluorouracil

Contraindications

  • Poor nutritional state.205

  • Depressed bone marrow function.205

  • Potentially serious infections.205

  • Known hypersensitivity to fluorouracil.205

Warnings/Precautions

Warnings

Maximum Dosage.

Do not exceed 800 mg daily.205

Poor Risk Patients

Use extreme caution in patients with history of high-dose pelvic irradiation, previous use of alkylating agents, widespread bone marrow metastases, impaired hepatic or renal function.205

Dipyrimidine Dehydrogenase Activity Deficiency

Deficiency of dipyrimidine dehydrogenase activity may cause prolonged fluorouracil clearance and toxicity.205

Severe, unexpected toxic reactions (including stomatitis, diarrhea, neutropenia, and neurotoxicity) have been reported.205

Rechallenge with fluorouracil (at a reduced dosage) has caused recurrent, progressive toxicity and increased morbidity.205

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.205

Advise women to avoid becoming pregnant.205

Inform women who become pregnant while taking fluorouracil that there is a potential hazard to the fetus.205

Use during pregnancy only if the potential benefit justifies the risk to the fetus.205

Combination Therapy

Any therapy that adds stress, interferes with nutrition, or depresses bone marrow function will increase fluorouracil toxicity.205

Leucovorin and Levoleucovorin

Extreme caution when combined with leucovorin or levoleucovorin in geriatric or debilitated patients, since they are more likely to develop serious fluorouracil toxicity.214 286 395 (See Interactions and also see GI Toxicity under Cautions.)

Sensitivity Reactions

Hand-foot Syndrome

Palmar-plantar erythrodysesthesia (hand-foot syndrome); in some cases, with prolonged infusions of high dosages.201 206

Erythematous, desquamative rash that involves the hands and feet,201 206 may be accompanied by tingling or painful hands and feet, swollen palms and soles, and phalangeal tenderness.205

Effects may gradually disappear over 5–7 days after fluorouracil discontinuance.205

May be treated with oral pyridoxine therapy, but safety and efficacy of pyridoxine for this condition have not been fully established.205

General Precautions

Toxicity

Highly toxic, very low therapeutic index; therapeutic response is unlikely without some evidence of toxicity.a 205 (See Boxed Warning.)

May produce severe hematologic toxicity, GI hemorrhage, and even death.205 a

Severe toxicity most likely in poor risk patients, but fatality may occur even in those in relatively good condition.205

GI Toxicity

Discontinue promptly at first visible sign of stomatitis or esophagopharyngitis.205

Discontinue promptly for intractable vomiting.205

Discontinue promptly for diarrhea, frequent bowel movements, watery stools.205 Potential for diarrhea to result in rapid clinical deterioration and death in patients receiving reduced folates (leucovorin, levoleucovorin) concomitantly; close monitoring is required.214 286 315 395

Discontinue promptly for GI ulceration and bleeding.205

Hematologic Toxicity

Discontinue promptly for leukopenia (WBC < 3500/mm3) or rapidly falling WBC;205 a place in protective isolation and take appropriate measures for prevention of infection if the leukocyte count drops to < 2000/mm3.a

Discontinue promptly for thrombocytopenia (platelets < 100,000/mm3).205

Discontinue promptly for hemorrhage from any site.205

Specific Populations

Pregnancy

Category D.205 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether fluorouracil is distributed into milk.205 Discontinue nursing while receiving the drug; fluorouracil inhibits DNA, RNA, and protein synthesis.205

Pediatric Use

Safety and efficacy in children not established.205

Common Adverse Effects

Stomatitis, esophagopharyngitis, anorexia, nausea, vomiting, diarrhea, leukopenia (principally granulocytopenia), thrombocytopenia, anemia, alopecia, dermatitis (principally pruritic maculopapular rash).205 a

Interactions for Fluorouracil

Specific Drugs

Drug

Interaction

Comments

Leucovorin

Leucovorin potentiates cytotoxicity of fluorouracil in certain GI cancers215 216 218 219 220 221 222 223 224 225 230 253 262 263 265 266 267

Leucovorin enhances fluorouracil toxicity214 286

Used to therapeutic advantage in GI cancers200 201 202 203 204 212 215 216 218 219 220 230 253

Use concomitantly with extreme caution in geriatric or debilitated patients; more likely to develop serious toxicity214 286

Levoleucovorin

Levoleucovorin enhances therapeutic effects of fluorouracil in colorectal cancer395

Levoleucovorin enhances fluorouracil toxicity395

Used to therapeutic advantage in colorectal cancer395 397

Use concomitantly with extreme caution in geriatric or debilitated patients; more likely to develop serious toxicity214 286 315 395

Fluorouracil Pharmacokinetics

Distribution

Extent

Distributed into tumors, intestinal mucosa, bone marrow, liver, and other tissues.205 a

Readily crosses the blood-brain barrier (despite limited lipid solubility), and distributes into CSF and brain tissue.205 a

Usually higher concentration of fluorouracil or metabolites in tumor than in surrounding tissue or in corresponding normal tissue, and persists longer in some tumors than in the normal host tissues, perhaps due to impaired uracil catabolism; suggests some tumor specificity.a

Crosses the placenta in rats.205 Not known whether fluorouracil is distributed into human milk.205

Elimination

Metabolism

A small portion is anabolized in tissues to 5-fluoro-2′-deoxyuridine, then to active metabolite (5-fluoro-2′-deoxyuridine-5′-monophosphate).a

The major portion is degraded in the liver, to inactive metabolites (e.g., CO2, urea, α-fluoro-β-alanine, α-fluoro-β-guanidopropionic acid, and α-fluoro-β-ureidopropionic acid).a

Elimination Route

7–20% is excreted unchanged in urine within 6 hours; >90% of this in the 1st hour.a 205

Inactive metabolites are excreted as respiratory CO2 and (in urine) as urea, α-fluoro-β-alanine, α-fluoro-β-guanidopropionic acid, and α-fluoro-β-ureidopropionic acid.a

Half-life

About 16 minutes (range: 8–20 minutes) and is dose dependent; no intact drug is detected in plasma after 3 hours.205 a

Stability

Storage

Parenteral

Injection

Discard unused portion of 2.5 or 5 g pharmacy bulk package 1 hour after the vial has been entered.a

15–30°C;205 do not freeze, protect from light.a

Slight discoloration during storage does not adversely affect potency or safety.205 a

Fluorouracil precipitation occurs commonly, particularly following exposure to low temperatures.274 Dissolve precipitate by heating to 60°C and shaking vigorously; cool to body temperature before using.205 a

Ease of dissolution may depend on the crystal size and location (e.g., those lodged between the stopper and glass container).274 Attempts to dissolve precipitate with heat and agitation may be unsuccessful.274

Store in adequately heated areas during cold weather to minimize frequency of precipitation.274

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Amino acids 4.25%, dextrose 25%

Dextrose 5% in Ringer’s injection, lactated

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Bleomycin sulfate

Cyclophosphamide

Cyclophosphamide with methotrexate sodium

Etoposide

Floxuridine

Hydromorphone HCl

Ifosfamide

Methotrexate sodium

Mitoxantrone HCl

Vincristine sulfate

Incompatible

Carboplatin

Ciprofloxacin

Cisplatin

Cytarabine

Diazepam

Doxorubicin HCl

Epirubicin HCl

Fentanyl citrate

Leucovorin calcium

Metoclopramide HCl

Morphine sulfate

Y-site CompatibilityHID

Compatible

Allopurinol sodium

Amifostine

Anidulafungin

Aztreonam

Bleomycin sulfate

Cisplatin

Cyclophosphamide

Doripenem

Doxorubicin HCl

Doxorubicin HCl liposome injection

Etoposide phosphate

Fludarabine phosphate

Furosemide

Gemcitabine HCl

Granisetron HCl

Heparin sodium

Hydrocortisone sodium succinate

Leucovorin calcium

Linezolid

Mannitol

Melphalan HCl

Methotrexate sodium

Metoclopramide HCl

Mitomycin

Paclitaxel

Palonosetron HCl

Pemetrexed disodium

Piperacillin sodium–tazobactam sodium

Potassium chloride

Propofol

Sargramostim

Teniposide

Thiotepa

Vinblastine sulfate

Vincristine sulfate

Incompatible

Aldesleukin

Amphotericin B cholesteryl sulfate complex

Droperidol

Filgrastim

Gallium nitrate

Topotecan HCl

Vinorelbine tartrate

Variable

Ondansetron HCl

Actions

  • Precise mechanisms of action of fluorouracil have not been fully elucidated.a

  • May interfere with DNA synthesis, RNA processing, and protein synthesis.358

  • Main mechanism may be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5–10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex, which inhibits the formation of thymidylate from uracil, interfering with DNA synthesis.358

  • In addition, FUTP can be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis.358

Advice to Patients

  • Advise patients about expected toxic effects, especially oral manifestations.205 a

  • Advise patients that alopecia is possible, but usually transient.205

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.205 a

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.205 a

  • Importance of informing patients of other important precautionary information. 205 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Fluorouracil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV use

50 mg/mL*

Adrucil

Teva

Fluorouracil Injection

50 mg/mL (2.5 or 5 g) pharmacy bulk package*

Adrucil

Teva

Fluorouracil Injection

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Fluorouracil 5GM/100ML Solution (APP PHARMACEUTICAL): 50/$18.99 or 100/$29.97

Fluorouracil 50MG/ML Solution (APP PHARMACEUTICAL): 50/$25.99 or 100/$39.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 9, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

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