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Drug Monographs
Treatment Regimens

Scientific Name:
FLUOROURACIL CONTINUOUS INFUSION (see also Fluorouracil)
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)
   hand-foot syndrome
   skin problems (pruritic maculopapular rash, dry skin, photosensitivity and hyperpigmentation, nail banding or loss)
   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

• Continuous IV (improved therapeutic index over direct IV).

Administration

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

For inpatient administration:
• Mix dose in 1000mL Normal Saline, infuse at over specified time
• Protect from light

IV Compatibility

Normal saline, dextrose 5%

Dosing

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

Pediatric:
IV infusion: q3w: 800-1200 mg/m² continuous IV over 24-120 hours

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

• Brand Name: Adrucil® Vials with 500mg/10mL, 5000mg/100mL • Generic products available • Do NOT Refrigerate

Pharmaceutical Considerations

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.
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.

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

Availability & Funding

Administrative Information (Nova Scotia)

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



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