fluorouracil (Rx)

1-10%

Loss of appetite

Headache

Nausea

Vomiting

Diarrhea

Mucositis

Myelosuppression

Alopecia

Photosensitivity

Hand-foot syndrome

Maculopapular eruption (pruritic)

Frequency Not Defined

Angina

Coronary arteriosclerosis

Thrombophlebitis

Darkening of veins

Gastrointestinal ulcer

Increased alkaline phosphatase

Increased LFTs

Hyperbilirubinemia

Hypercholesterolemia (increased LDH)

Anaphylaxis

Nystagmus

Ophthalmic findings

Contraindications

Hypersensitivity

Poor nutritional status

Myelosuppression

Serious infection

Recent serious surgery

Dihydropyrimidine Dehydrogenase (DPD) deficiency

Cautions

Discontinue in case of stomatitis, esophagopharyngitis, leukopenia, thrombocytopenia, intractable vomiting, GI bleeding, hemorrhage, diarrhea

Prior alkylating agent use, CAD, hepatic/renal impairment

Avoid pregnancy

Cardiotoxicity, usually ischemic in nature, has been seen with highdose infusions

Case reports of cardiomyopathy and acute decreases in LVEF Cardiotoxicity is more common with IV 5FU compared to oral capecitabine

Pregnancy Category: D

Lactation: excretion in milk unknown; do not nurse

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Inhibits DNA synthesis during S phase by inhibition of thymidylate synthetase

Pharmacokinetics

Half-Life: 16 min

Onset: 2-7 d, but may take up to 12 wk

Duration: 24 hr

Metabolism: liver

Metabolites: urea, fluorouracil, dihydrofluorouracil, expired CO2 metabolite

Excretion: urine

Pharmacogenomics

Dihydropyrimidine dehydrogenase (DPD), an enzyme encoded by the DPYD gene, is the rate-limiting step in pyrimidine catabolism and deactivates >80% of 5FU standard doses and the 5FU prodrug capecitabine

Contraindicated in patients with DPD deficiency; causes severe toxicity with conventional doses (ie, grade III/IV toxicity and potentially fatal neutropenia, mucositis, and diarrhea)

Because true DPD deficiency is rare and because the clinical implications of partial deficiency are still unclear, screening for mutations prior to initiating therapy is not warranted

Genetic testing laboratories

• The following companies currently offer testing for DPYD*2A mutations
• EntroGen (http://www.entrogen.com)
• Myriad (http://www.myriadtests.com)
• LabCorp (http://www.labcorp.com)
• Molecular Diagnostics Laboratories (http://www.mdl-labs.com)

IV Incompatibilities

Additive: carboplatin, cisplatin, cytarabine, diazepam, doxorubicin, epirubicin, fentanyl, leucovorin, metoclopramide, morphine sulfate

Syringe: doxorubicin (at high conc of doxo & 5FU, compatible at lower conc), droperidol, epirubicin

Y-site: aldesleukin, amphotericin B cholesteryl SO4, droperidol, filgrastim, ondansetron(?), topotecan, vinorelbine

IV Compatibilities

Solution: compatible w/ most common solvents

Additive: bleomycin, cyclophosphamide, cyclophosphamide/methotrexate, etoposide, floxuridine, hydromorphone, ifosfamide, methotrexate, mitoxantrone, vincristine

Syringe: bleomycin, cisplatin, cyclophosphamide, furosemide, heparin, leucovorin, methotrexate, metoclopramide, mitomycin, vinblastine, vincristine

Y-site: (partial list) allopurinol, furosemide, granisetron, heparin, hydrocortisone-Na-succinate, leucovorin, linezolid, metoclopramide, piperacillin/tazobactam, KCl, propofol, vit B/C

IV Preparation

IV Push: dose/syringe (concentration: 50 mg/mL); max syringe size for IVP is 30 mL syringe and syringe should be <75% full

Continuous IV Infusion/IVPB: dose/50-1000 mL D5W or NS; syringe and solution are stable for 72 hr at 4 to 25°C

IV Administration

Direct IV push injection (50 mg/mL solution needs no further dilution) or by IV infusion

Toxicity may be reduced by giving the drug as a constant infusion

Bolus doses may be administered by slow IVP or IVPB

Warm to body temperature before using

Continuous IV infusion may be administered in D5W or NS

Solution should be protected from direct sunlight

5-FU may also be administered intra-arterially or intra-hepatically

Use plastic IV containers for continuous infusions (stable in plastic IV bags than in glass bottles)

Storage

Store intact vials at room temp & protect from light

Slight discoloration does not usually denote decomposition

Don't use cloudy solutions

• If crystals form, redissolve by warming

Don't refrigerate