Fluorouracil - Drug Monograph

Introduction

Fluorouracil (5-FU) is a fluorinated pyrimidine analog antineoplastic agent that has been a cornerstone of cancer chemotherapy since its FDA approval in 1962. As an antimetabolite, it interferes with nucleic acid synthesis and is widely used in the treatment of various solid tumors, particularly gastrointestinal malignancies, breast cancer, and cutaneous neoplasms. Fluorouracil remains one of the most extensively studied and utilized chemotherapeutic agents worldwide.

Mechanism of Action

Fluorouracil exerts its cytotoxic effects through multiple mechanisms. After intracellular conversion to active metabolites, primarily fluorodeoxyuridine monophosphate (FdUMP), it inhibits thymidylate synthase, thereby disrupting DNA synthesis and repair. Additionally, fluorouracil metabolites can be incorporated into RNA, interfering with RNA processing and function. The drug is cell cycle-specific, with primary activity during the S-phase of cell division.

Indications

FDA-approved indications include:

• Colorectal cancer (adjuvant and metastatic)
• Breast cancer (after failure of primary therapy)
• Gastric cancer
• Pancreatic cancer
• Topical treatment of actinic keratoses and superficial basal cell carcinomas

Off-label uses include:

• Anal cancer
• Esophageal cancer
• Hepatobiliary cancers
• Ovarian cancer
• Head and neck cancers

Dosage and Administration

• IV bolus: 370-425 mg/m² daily for 5 days every 4-5 weeks
• IV continuous infusion: 1000 mg/m²/day for 4-5 days every 3-4 weeks
• Commonly used in combination regimens (e.g., FOLFOX, FOLFIRI)

• 5% cream: Apply twice daily for 2-6 weeks for actinic keratoses
• 5% solution: Apply once or twice daily for superficial basal cell carcinomas

• Renal impairment (CrCl <50 mL/min)
• Hepatic impairment
• Elderly patients
• Patients with dihydropyrimidine dehydrogenase (DPD) deficiency

Pharmacokinetics

Contraindications

• Known hypersensitivity to fluorouracil or any component of the formulation
• Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency
• Pregnancy (unless potential benefit justifies potential risk to fetus)
• Bone marrow suppression (severe)
• Poor nutritional status
• Serious infection

Warnings and Precautions

• Myelosuppression: Monitor blood counts regularly
• Cardiotoxicity: May cause myocardial ischemia, angina, or MI
• Neurotoxicity: Acute cerebellar syndrome reported
• DPD deficiency: Screen for DPD deficiency due to risk of severe toxicity
• Hand-foot syndrome (palmar-plantar erythrodysesthesia)
• Mucositis and diarrhea: May be severe and require dose modification
• Photosensitivity: Avoid excessive sun exposure

Drug Interactions

• Leucovorin: Enhances toxicity and efficacy through thymidylate synthase inhibition
• Warfarin: Increased anticoagulant effect; monitor INR closely
• Phenytoin: Altered phenytoin levels; monitor serum concentrations
• Metronidazole: May increase fluorouracil toxicity
• Cimetidine: May increase fluorouracil concentrations

• Live vaccines: Avoid concurrent administration
• Other myelosuppressive agents: Additive bone marrow toxicity
• Interferon-alpha: Increased fluorouracil toxicity

Adverse Effects

• Myelosuppression (neutropenia, leukopenia, thrombocytopenia)
• Nausea/vomiting (30-50%)
• Diarrhea (30-50%)
• Mucositis/stomatitis (15-40%)
• Alopecia (10-30%)
• Dermatological reactions (15-20%)
• Hand-foot syndrome (5-15%)

• Febrile neutropenia
• Severe diarrhea leading to dehydration
• Cardiotoxicity (angina, MI, arrhythmias)
• Neurotoxicity (cerebellar ataxia, confusion)
• Ocular toxicity (lacrimal duct stenosis, conjunctivitis)
• Hyperammonemic encephalopathy
• Anaphylaxis

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel (renal and hepatic function)
• Cardiac evaluation in high-risk patients
• DPD deficiency testing (consider in all patients)

• CBC weekly or prior to each cycle
• Renal and hepatic function periodically
• Signs of mucositis, diarrhea, hand-foot syndrome
• Cardiac monitoring in patients with risk factors
• Nutritional status and hydration

• Secondary malignancies (rare)
• Cardiac function in survivors
• Neurocognitive function

Patient Education

• Importance of adherence to scheduled treatments and monitoring appointments
• Potential side effects and when to seek medical attention (fever, severe diarrhea, mouth sores)
• Proper hand hygiene and infection prevention measures
• Sun protection measures due to photosensitivity
• Management of hand-foot syndrome (moisturizers, avoiding friction)
• Nutritional support during treatment
• Contraception requirements during and after treatment
• Avoidance of live vaccines during treatment
• Reporting any new or worsening symptoms immediately

• Application technique and frequency
• Expected skin reactions
• Avoidance of contact with eyes, nose, and mouth
• Proper hand washing after application

References

1. American Society of Health-System Pharmacists. AHFS Drug Information. Fluorouracil monograph. 2. National Comprehensive Cancer Network (NCCN) Guidelines. Various cancer-specific guidelines. 3. Fluorouracil [package insert]. Lake Forest, IL: Hospira Inc; 2019. 4. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330-338. 5. Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet. 1989;16(4):215-237. 6. USP DI. Fluorouracil (Systemic). Micromedex Solutions. 7. FDA Approved Drug Products: Fluorouracil injection. 8. Grem JL. 5-Fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development. Invest New Drugs. 2000;18(4):299-313.