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Document Type

Drug Monographs
Treatment Regimens

Scientific Name:
FLUOROURACIL (see also Fluorouracil Continuous Infusion)
Brand Name(s):
5FU, Adrucil®

Drug Monograph

Pharmacology

Mechanism of Action

5-Fluorouracil is a fluorinated pyrimidine antimetabolite. The nucleotides generated intracellularly exert a cytotoxic effect by inhibiting thymidylate synthase (TS) resulting in inhibition of DNA synthesis. Incorporation into RNA also interferes with RNA synthesis and function.

Pharmacokinetics

Oral Absorption:
Varies from 28-100% as a result of dihydropyrimidine dehydrogenase (DPD). Oral 5-FU is not generally used, but is being investigated in combination with inhibitors of DPD.
Distribution:
into all body water by passive diffusion, crosses placenta, high and persistent levels in malignant effusions; excretion in breast-milk unknown cross blood brain barrier?  Yes
Vd:  0.25 L/kg, 8.84 L/m2; 12-89% of body water; 13-18 L 
PPB: 8-12%
Metabolism:
intracellular (anabolic): to active nucleotides (FdUMP, FUTP)
hepatic and extrahepatic (catabolic): via DPD to dehydrofluorouracil (DHFU) which is subsequently metabolized to fluoro-b-alanine (FBAL)
metabolite(s): active- Yes (FdUMP, FUTP)
  inactive- Yes
Excretion:
excreted as respiratory CO2, <5% excreted unchanged in urine; the majority of the drug is eliminated by metabolism
urine: <5% unchanged  t½ 8-13 minutes  Cl 0.6-2.3 L/min, 16 mL/min/kg,
 women 155 L/h/m2, men 179 L/h/m2

Side Effects

IMMEDIATE ONSET (hours to days)
* anaphylaxis (rare- Symptoms: angioedema, hypotension)
   vein irritation (phlebitis)
   nausea and vomiting (usually mild)
* heart problems (rare, angina pectoris, ECG changes)
   radiation recall reaction (rare)
EARLY ONSET  (days to weeks)
* myelosuppression: neutropenia, leukopenia nadir 7-14 days, recovery 22-24 days); thrombocytopenia
   mouth sores (stomatitis, may be severe with high dose leucovorin)
* diarrhea (may be severe with high dose leucovorin), anorexia, esophagitis
   hair loss (alopecia, usually mild)
   skin problems (pruritic maculopapular rash, dry skin, photosensitivity and hyperpigmentation, nail banding or loss, hand-foot syndrome)
   eye problems (oculomotor disturbances [weakness of convergence and divergence], lacrimation)
   reddening, blistering of skin (topical use)
DELAYED/LATE ONSET (weeks to years)
   eye problems (tear duct fibrosis)
   central nervous system problems-rare (ataxia, acute cerebellar syndrome, acute encephalopathy)

Therapeutics

Approved Indications

• Actinic keratosis        
• Bladder cancer        
• Breast cancer        
• Cervical cancer
• Colorectal cancer        
• Gastric cancer
• Head and neck cancer
• Ovarian cancer        
• Pancreatic cancer
• Prostate cancer

OTHER ONCOLOGY USES (Not Approved)
• Hepatic cancer
• Endometrial cancer        
• Lung cancer, non-small cell

Routes

• Direct IV  (over 1-2 minutes)
• Intermittent IV (in 50-100 mL over 10-30 minutes)
• Continuous IV (improved therapeutic index over direct IV)

Administration

• Slow push through sidearm of free flowing IV (5% Dextrose, Normal Saline) over 1-2 minutes (administering nurse should be certified to administer IV push chemotherapy agents)
• May be given by direct IV push, followed by a Normal Saline flush, if no IV line has been set up
• May be mixed in 50mL minibag (5% Dextrose, Normal Saline); Infuse through sidearm of free flowing IV over 10-15 minutes 
 
For inpatient administration:
• Mix dose in 1000mL Normal Saline, infuse at over specified time
 Fluorouracil Infusion
• Continuous infusion using ambulatory infusion pump
• Infuse through central venous access device or PICC line, if available
• Infuse through patent peripheral venous catheter, if infusion for only 3-5 days; Inspect peripheral infusion sites daily and replace if evidence of irritation or extravasation
Protect from light

IV Compatibility

normal saline, dextrose 5%

Dosing

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

Pediatric
IV bolus: q3w: 600 mg/m²

Dose Adjustment Criteria

Marked hepatic dysfunction
Omit dose if bilirubin elevated above 85µmol/L
(Suggested action)

Antiemetic Risk

LOW RISK (Less than 10% of patients)
• No routine antiemetic pre-chemotherapy or post-chemotherapy

Contraindications

• Pregnancy and breast feeding. • Low WBC, RBC, platelets (myelosuppression).

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
• Complete blood count including differential, platelets and hemoglobin (CBC) before each cycle of treatment
• Clinical assessment of stomatitis; oral examination upon patient complaint of a sore mouth
For Continuous Infusion:
• Skin assessment, especially extremities

SUGGESTED CRITERIA
• Baseline liver function tests [serum alkaline phosphatase, GGT, ALT, AST & Bilirubin levels, serum albumin] (if severe organ failure suspected)
• Baseline renal function tests [serum creatinine, electrolytes & BUN] (if severe organ failure suspected)
For Continuous Infusion:
Local Site Toxicity ratings, if incident of phlebitis
 
LOCAL SITE TOXICITY
0. None 
1. Pain
2. Pain & inflammation; phlebitis
3. Ulceration
4. Plastic surgery
Upon Patient Complaint Or Clinical Event

Extravasation Hazard

Vein pigmentation (rare); thrombophlebitis (rare).

Significant Interactions

Allopurinol, amifostine, calcium folinate, cimetidine, leucovorin, metronidazole, morphine, pyridoxine, sorivudine, thiazide diuretics, warfarin, other antineoplastic agents.

Product Information

Commercial Product Description

• Vials with 500mg/10mL, 5000mg/100mL • Generic products available • Do NOT Refrigerate

Pharmaceutical Considerations

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

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.

Handling Risk Level

Pregnancy DKNOWN HAZARDOUS DRUG
FDA Pregnancy Risk Factor D

  • This drug must be handled using precuations outlined in CCNS Policies for Occupational Safety and Administering Cancer Chemotherapy

Note

HANDLING RISK LEVEL:

HAZARD RISK LEVEL 2
FDA Pregnancy Risk Factor D
• This drug must be handled using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy
• Go to "Additional Information" tab (above) for links to CCNS Policies

Availability & Funding

Administrative Information (Nova Scotia)

• CCNS Provincial Formulary Status- Basic Level • Go to "Additional Information" tab (above) for links to the Provincial Formulary of Cancer Drugs • Pharmacare Formulary Status- Formulary (red) NOTE: It is recommended to limitordering of this medication to standard preprinted order forms, for patient safety.



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