Does Topical Fluorouracil Cause Skin Irritation?
Yes, topical fluorouracil consistently causes skin irritation as an expected pharmacological effect of the medication, with local reactions occurring in the vast majority of treated patients. 1, 2
Mechanism and Expected Reactions
Topical 5-FU produces inflammation as part of its therapeutic mechanism by damaging dividing basal layer cells and blocking DNA synthesis. 1 The British Association of Dermatologists explicitly states that when used topically, 5-FU "produces inflammation and occasionally erosions." 1
Common Local Skin Reactions
The FDA drug label identifies the most frequent adverse reactions as local and related to the drug's pharmacological activity, including: 2
- Burning
- Crusting
- Allergic contact dermatitis
- Pruritus (itching)
- Rash
- Soreness
- Ulceration
- Erythema (redness)
- Scaling
- Erosions
Severity and Clinical Significance
The severity of local skin reactions correlates directly with treatment efficacy. 3 A 2025 analysis of 397 patients demonstrated that those achieving complete or partial clearance (80.9%) had more severe local skin reactions during treatment compared to those with poor clearance. 3 Specifically:
- Severe erythema at week 2 was significantly associated with better lesion clearance compared to mild erythema 3
- At week 4, both severe and moderate erythema, moderate scaling, and moderate pruritus were significantly associated with higher clearance rates 3
- Severe local skin reactions did not compromise treatment efficacy 3
Frequency and Tolerability
In comparative studies, adverse events occurred in 100% of patients treated with 5% fluorouracil twice daily, with facial irritation being the most common reaction. 4 The irritation can be severe enough to cause treatment discontinuation—in one study, 3 of 10 patients discontinued 5% fluorouracil early due to intolerance. 4
Concentration-Dependent Effects
Lower concentrations produce less severe irritation: 4
- 0.5% fluorouracil once daily: adverse events in 4 of 11 patients (36%), all patients completed treatment
- 5% fluorouracil twice daily: adverse events in 10 of 10 patients (100%), 30% discontinued early
Uncommon Distant Reactions
While local irritation is expected and common, rare distant skin reactions can occur despite application to localized areas: 5, 6
- Scrotal dermatitis has been reported after chest application 5
- Seborrheic dermatitis-like eruptions at distant sites 6
- These reactions resolve upon discontinuation and recur with rechallenge 5, 6
Additional Adverse Effects
Beyond local irritation, the FDA label notes less common reactions including: 2
- Blistering and suppuration
- Telangiectasia
- Hyperpigmentation or hypopigmentation (with prolonged use) 1
- Systemic effects: metallic taste 7, emotional upset, insomnia 2
Clinical Management Pearls
Patients must be counseled that local skin irritation is an expected and often necessary part of treatment, not a reason for immediate discontinuation. 3 The British Association of Dermatologists notes that the extent of side-effects is not wholly predictable, with some patients manifesting extreme reactions and others very little, but clinical response is largely proportional to side-effects. 1
For patients with thin or fragile skin (particularly elderly patients on lower extremities), consider observation rather than intervention due to poor healing potential. 1