5-fluorouracil

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SYNONYM(S): 5-Fluorouracil, 5FU

COMMON TRADE NAME(S): Adrucil®, Fluorouracil Roche®, Efudex® Cream, Fluoroplex® Topical.

CLASSIFICATION: Antimetabolite, cytotoxic1

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION: [1,2]

Fluorouracil was developed in 1957 based on the observation that tumour cells utilized the base pair uracil for DNA synthesis more efficiently than did normal cells of the intestinal mucosa. It is a fluorinated pyrimidine that is metabolized intracellulary to its active form, fluorodeoxyuridine monophophate (FdUMP). The active form inhibits DNA synthesis by inhibiting the normal production of thymidine. Fluorouracil is cell cycle phase-specific (S-phase).

PHARMACOKINETICS: [2,3,4,5,6,7,8,9,10,11]

 
Oral Absorption 28-100%
Distribution into all body water by passive diffusion, crosses placenta, high and persistent levels in malignant efusions
  cross blood brain barrier? yes
  Vd 0.25 L/kg, 8.84 L/m2, 12-89% of body water
  PPB 8-12%
Metabolism activated in target cells, catabolized in liver, most of dose (80%) eliminated by liver
  active metabolite(s) yes
  inactive metabolite(s) yes
Excretion 60-80% excreted as respiratory CO2, 2-3% by biliary system
  urine 15% as intact drug within 6 hours
  t½ 10-20 minutes
  Cl 0.6-2.3 L/min, 16 mL/min/kg,

women 155 L/h/m2, men 179 L/h/m2

USES: [3,12,13]

* Breast cancer
* Colorectal cancer
* Gastric cancer
  Hepatic cancer		 Less frequent uses include:
* Actinic keratoses
* Bladder cancer
* Cervical cancer
  Endometrial cancer
* Head and neck cancer
  Lung cancer, non-small cell
* Ovarian cancer
* Pancreatic cancer
* Prostate cancer

* Health Protection Branch approved indication.

SPECIAL PRECAUTIONS: [3]

Fluorouracil has potential mutagenic and carcinogenic effects. Its safe use in pregnancy and its effects on fertility have not been established. Breast feeding is not recommended due to the potential secretion into breast milk.

SIDE EFFECTS: [3,10,11]

ORGAN SITE

SIDE EFFECT

ONSET
cardiovascular asymptomatic ECG changes (67%) I      
  angina pectoris (2-3%) I      
central nervous system acute cerebellar syndrome (rare)   E D  
  acute encephalopathy (rare)   E D  
dermatologic alopecia (mild)   E    
  hyperpigmentation (over veins used)   E    
  rash (extremities, sometimes on trunk)   E    
  nail changes   E    
  photosensitivity   E    
  palmar-plantar erythrodysesthesia (hand-foot syndrome)   E    
  radiation recall reaction (rare) I      
  erythema, necrosis (topical application) I E    
extravasation hazard none        
gastrointestinal mild nausea and vomiting I      
  stomatitis   E    
  diarrhea   E    
hematologic myelosuppression

nadir 7-14 days, recovery 22-24 days

   E    
  immunosuppression   E    
  megaloblastosis   E    
hypersensitivity Type I (anaphylactoid, rare) I      
injection site chemical phlebitis I      
ocular excessive lacrimation I      
  conjunctivitis I      
  tear duct fibrosis     D  

Dose-limiting side effects are underlined.
I = immediate (onset in hours to days); E = early (days to weeks);
D = delayed (weeks to months); L = late (months to years)

Following IV infusion, stomatitis and diarrhea occur most commonly. Diarrhea may be profuse and life threatening following administration of leucovorin with fluorouracil. Leukopenia is the usual dose-limiting toxicity after IV bolus administration.

Excessive lacrimation occurs frequently. Transient blurring of vision, eye irritation and excessive nasal discharge have also been reported. The onset of eye symptoms may occur at any time during treatment. Fluorouracil has been demonstrated in tear fluid causing acute and chronic conjunctivitis that can lead to tear duct fibrosis.

Acute cerebellar syndrome is manifested as ataxia of the trunk or extremities, disturbance of gait and speech, coarse nystagmus and dizziness. The ataxia syndrome is related to peak plasma levels of the drug rather than to cumulative dose, and is therefore more common with bolus doses than with infusions.

Palmar-plantar erythrodysesthesia or hand-foot syndrome has been noted with protracted and high dose continuous infusion (23-82%). The syndrome begins with dysesthesias of the palms and soles that progress to pain and tenderness. There is associated symmetrical swelling and erythema of the hand and foot. Treatment with 50 or 150 mg of pyridoxine daily has been associated with reversal of the syndrome. The syndrome resolves with cessation of drug infusion.

Fluorouracil has the potential to enhance radiation injury to tissues. While often called radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of the fluorouracil. Recurrent injury to a previously radiated site may occur weeks to months following radiation.

When applied to a lesion, the following occurs: erythema, usually followed by vesiculation, erosion, ulceration, necrosis and epithelization. The lower frequency and intensity of activity in adjacent normal skin indicates a selective cytotoxic property. The cream is preferably applied with a nonmetal applicator or glove. If applied with the fingertips, the hands should be washed immediately afterwards. Apply with care near the eyes, mouth and nose. An occlusive dressing is not essential, and may increase the incidence of inflammatory reactions in adjacent normal skin. Therapy is usually continued to reach the erosion, necrosis and ulceration stage (2-4 weeks), after which healing occurs over 4-8 weeks. The most frequent local reactions are pain, pruritus, hyperpigmentation and burning at the application site. Avoid prolonged exposure to ultraviolet light while under treatment as the intensity of the reaction may be increased.

INTERACTIONS: [3,7,14,15,16]

AGENT

EFFECT

MECHANISM

MANAGEMENT
allopurinol decreased toxicity of fluorouracil possibly inhibition of thymidine phosphorylase, which activates fluorouracil may decrease the hematological toxicity of fluorouracil, but results are conflicting
cimetidine increased serum concentrations of fluorouracil appears to interfere with fluorouracil metabolism observe for increased toxicity of fluorouracil
leucovorin

 

 increased cytotoxic and toxic effects of fluorouracil leucovorin stabilizes the bond to thymidylate synthetase some protocols are designed to take advantage of this effect; monitor toxicity closely
metronidazole enhanced toxicity of fluorouracil decreased clearance of fluorouracil monitor for increased toxicity of fluorouracil
oxaliplatin2 no influence on fluorouracil pharmacokinetics    
thiazide diuretics increased myelosuppression decreased renal excretion of fluorouracil consider an alternative antihypertensive
warfarin3,4 increased effect and toxicity of warfarin possibly protein displacement, inhibition of warfarin metabolism, or inhibition of clotting factor synthesis check baseline INR; monitor weekly INR during, and for one month after, fluorouracil therapy; increase frequency and duration of monitoring if INR unstable; adjust warfarin dose as needed

SUPPLY AND STORAGE: [3]

Topical preparations: 1% topical solution; 1% or 5% cream, store at room temperature.

SOLUTION PREPARATION AND COMPATIBILITY: [3,17,18,19,20,21]

Injection: 50 mg/mL (5 mL, 10 mL, 50 mL and 100 mL vial or amp). Clear, colourless to faint yellow solution; preservative-free. May contain sodium hydroxide for pH adjustment. Store at room temperature protected from intense incandescent light and sunlight. If a precipitate occurs due to storage at low temperature, resolubilize by heating to 60° C with vigorous shaking and allow to cool to body temperature before using. Although slight discolouration does not affect potency, a dark yellow indicates greater decomposition and such solutions should not be used.

Solution for injection: One manufacturer (Pharmacia) recommends that unused portions of vials be discarded within 8 hours of puncture, since the solution is preservative-free.

Stability in syringes: Fluorouracil does not adsorb to polypropylene syringes or polyethylene syringe plungers. Benvenuto reported that fluorouracil in D5W was stable for at least 30 days at room temperature in plastic syringes. One manufacturer (Pharmacia) recommends that syringes be stored at room temperature and used within 24 hours of withdrawal from vials.

Undiluted solution in ambulatory pumps: Under simulated ambulatory infusion conditions, three brands of undiluted fluorouracil, including the Roche brand, demonstrated stability of 7 days at 37° C in portable infusion pump reservoirs (Pharmacia Deltec CADD-1, Model 5100; Cormed II, Model 10500; Medfusion Infumed 200; and Pancretec Provider I.V., Model 2000). However, the Roche brand at 25° C demonstrated a fine precipitate 48-96 hours after pumping action began.

Diluted solution for infusion: Solutions of 1-2 g/L NS, D5W and dextrose-saline in glass and PVC containers were physically and chemically stable for 8 weeks at room temperature in the dark and exposed to fluorescent light. A higher concentration (8 g/L) in D5W was stable for only 7 hours in glass containers but for 43 hours in PVC containers. Fluorouracil apparently does not adsorb to PVC, polyethylene or silastic containers or tubing but may be extensively adsorbed to glass containers.

Fluorouracil (Roche) 500 mg/50 mL in D5W in a PVC reservoir of an ambulatory infusion pump (Travenol PL 145 MVP) demonstrated little change in drug content in 7 days at 25° C, but drug concentration increased progressively over 16 weeks (probably due to water evaporation from the bag). No change was seen when the reservoirs were stored for 16 weeks at 5° C. Fluorouracil (Roche) 500 mg/60 mL in D5W in an elastomeric reservoir (Travenol Infusor) exhibited less than 10% loss after 16 weeks' storage at 5° C.

Filtration: Little or no loss of fluorouracil 10-75 mcg/mL was seen when the solution was filtered through either cellulose nitrate/cellulose acetate ester (Millex OR) or Teflon (Millex FG) filters.

Some admixtures with heparin, leucovorin or prednisolone sodium phosphate may be compatible. It is recommended that fluorouracil not be mixed with other drugs. Incompatible with carboplatin, cisplatin, cytarabine, diazepam, doxorubicin, epirubicin, methotrexate and ondansetron.

PARENTERAL ADMINISTRATION: [2,22,23,24,25]

 

BCCA administration guidelines noted in bold, italics
Subcutaneous investigational, 89% bioavailability
Intramuscular not recommended, may be irritating
Direct intravenous push over 1-2 minutes into side arm of running IV
Intermittent infusion in 50 mL over 10-30 minutes or in 300-500 mL (approximately 2 mg/mL) over 4 hours
Continuous infusion add daily dose to 1 L appropriate solution and give over 24 hours or give entire dose via ambulatory pump or infusor; improves therapeutic index over bolus injection but does not appear to increase efficacy
Intraperitoneal by physician only; has been used, not generally recommended
Intrapleural has been used, not generally recommended
Intrathecal contraindicated due to neurotoxicity
Intra-arterial has been used, not generally recommended
Intravesical no information available on this route

DOSAGE GUIDELINES: [2,3,13,22,26,27,28,29,30,31]

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of white blood cell count. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy.

Adults:  
IV bolus: 450 mg/m2/day x 5 days then on day 29 450 mg/m2 q1w
q1w: 350-600 mg/m2
q3w: 600 mg/m2
q3-4w: 250-600 mg/m2 day x 5 days
q4w: 400-500 mg/m2 days 1 & 8
IV infusion: q1w: 2.6 g/m2 over 24 hours
q1w: 30 mg/kg/day x 2 days
q3-4w: 400-1000 mg/m2/day x 4-10 days as continuous infusion
daily: 200-300 mg/m2 x 5-18 weeks as continuous infusion
Dosage in myelosuppression: modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Myelosuppression"
Dosage in renal failure: no adjustment required
Dosage in hepatic failure: omit if bilirubin >85 µmol/L
   
Topical: daily: x 1-4 weeks. Glove or non-metal applicator preferred. If fingertips used, wash hands immediately. Stop when erosion evident, usually 2-4 weeks. Allow 1-2 months for healing.
Total area treated at one time should not exceed 500 cm2 (23x23 cm). Larger areas should be treated one section at a time.
   
Children:  
IV bolus: q3w: 600 mg/m2
IV infusion: q3w: 800-1200 mg/m2 continuous IV over 24-120 hours

BIBLIOGRAPHY:

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  12. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther 1993;35:43-50.
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  21. Trissel LA, Tramonte SM, Grilley BJ. Visual compatability of ondansetron hydrochloride with selected drugs during simulated Y-site injection. Am J Hosp Pharm 1991;48:988-92.
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  23. Stagg RJ, et al. Alternating hepatic intra-arterial floxuridine and fluorouracil: a less toxic regimen for treatment of liver metastases from colorectal cancer. J Natl Cancer Inst 1991;83(6):423-8.
  24. Kajanti M, et al. Intra-arterial and intraveous use of 4' epidoxorubicin combined with 5-fluorouracil in primary hepatocellular carcinoma. A randomized comparison. Am J Clin Onc 1992;15(1):37-40.
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  28. Green DM, Krischer JP, Bell B, et al. Phase I study of 120-hour continuous intravenous infusion of 5-fluorouracil in pediatric patients with recurrent solid tumors: A Pediatric Oncology Group Study. Med Pediatr Oncol 1990;18:321-4.
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REFERENCES:
  1. National Institute for Occupational Safety and Health (NIOSH). Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Healthcare Settings. Cincinnati, OH; 25 March 2004.
  2. Joel SP, Papamichael D, Richards F, et al. Lack of pharmacokinetic interaction between 5-fluorouracil and oxaliplatin.[see comment]. Clin Pharmacol Ther 2004;76(1):45-54.
  3. Tatro D, editor. Drug Interactions Facts on Disc. St. Louis: Facts and Comparisons; 2005.
  4. Masci G, Magagnoli M, Zucali PA, et al. Minidose warfarin prophylaxis for catheter-associated thrombosis in cancer patients: can it be safely associated with fluorouracil-based chemotherapy? 2003:736-9, 2003 Feb 15.
 

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