Phenytoin and Fluorouracil Topical: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Phenytoin
Fluorouracil Topical
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Increased phenytoin or fosphenytoin (prodrug of phenytoin) exposure and associated phenytoin or fosphenytoin toxicity
Interaction Deep Dive
Case reports have described phenytoin toxicity during concomitant use of capecitabine or fluorouracil7. Coadministration of capecitabine or doxifluridine or fluorouracil (prodrugs of capecitabine) or tegafur (prodrug of fluorouracil) and phenytoin or fosphenytoin (prodrug of phenytoin) may result in increased phenytoin or fosphenytoin exposure 34, and monitoring of phenytoin or fosphenytoin levels, with appropriate dosage adjustment, may be warranted 12. Monitor if concurrent chemotherapy is discontinued to ensure phenytoin or fosphenytoin dosage and levels are clinically sufficient 7.
Why it happens (mechanism)
Inhibition of CYP2C9-mediated metabolism of phenytoin
Literature reports
3 reports — tap to read
a) A 65-year-old male Asian patient with a 10-year history of generalized tonic clonic epilepsy, as well as Dukes' B adenocarcinoma of the colon, experienced an increase in serum phenytoin following palliative 5-fluorouracil/folinic acid (5FU/FA) at doses of 370 and 20 mg/m2 weekly. His epilepsy was controlled with phenytoin 300 mg and PHENobarbital 90 mg daily. Seven weeks after starting chemotherapy he was admitted with a 10 day history of progressive confusion, drowsiness, generalized weakness, and fatigue preventing him from walking. He was drowsy, dysarthric, had bilateral gaze evoked nystagmus and marked limb ataxia on examination. He was unable to stand unsupported. His serum phenytoin level was 162 mcmol/L (40-80). His phenobarbitone level was 89 mcmol/L (65-170). Phenytoin was withheld for 5 days until his serum level was less than 80 mcmol/L, and phenytoin toxicity resolved. When his serum level was 67 mcmol/L, phenytoin was restarted at a reduced dose of 230 mg daily. His serum phenytoin level increased to 75 mcmol/L on this dose before dropping to 22 mcmol/L 5 weeks after stopping chemotherapy 7.
b) A 60-year-old male patient with a history of post-traumatic generalized tonic clonic epilepsy was being treated with phenytoin 430 mg daily with stable phenytoin serum levels (75 mcmol/L). He was diagnosed with Dukes' C adenocarcinoma of the transverse colon and was started on adjuvant 5FU/FA at doses of 370 and 20 mg/m2 weekly. At 4 weeks post chemotherapy initiation, the patient presented with a 6-day history of progressive light-headedness and inability to stand unsupported. His phenytoin level was 213 mcmol/L. Phenytoin was withheld for 7 days until phenytoin levels reached 42 mcmol/L. Phenytoin 300 mg/day was restarted, and the serum phenytoin level rose from 42 to 118 mcmol/L. Phenytoin dose was further reduced to 100 mg/day and he was discharged with ongoing chemotherapy. Since his discharge from the hospital he has had a seizure associated with a subtherapeutic serum phenytoin level of 24 mcmol/L and his phenytoin dose has been increased to 200 mg daily 7.
c) A 45-year-old female patient with a greater than 10-year history of poorly controlled generalized tonic clonic epilepsy was taking phenytoin 400 mg daily, cloBAZam 10 mg and sodium valproate 1 gm twice daily. Serum phenytoin levels at this time were 141 mcmol/L. After developing breast cancer she underwent adjuvant treatment with IV cycloPHOSphamide, methotrexate, and 5-FU (CMF) chemotherapy. She was placed on palliative chemotherapy (DOXOrubicin, followed by DOCEtaxel, and twice daily capecitabine, completing two cycles) after her cancer progressed. The protocol used for CMF was: cycloPHOSphamide 100 mg/m2 day 1-14, methotrexate 40 mg/m2 days 1 and 8, 5-FU 600 mg/m2 days 1 and 8 in a 4 weekly cycle and capecitabine was prescribed at a dose of 1500 mg twice daily for 14 days, repeating 3 weekly. 6 weeks after starting therapy she was admitted with a 2 day history of an unsteady gate, recurrent falls, weakness, poor balance, and limb ataxia. Phenytoin level was 161 mcmol/L. Phenytoin was withheld for 5 days until level was under 80 mcmol/L and dose was reduced to 300 mg daily. She became lightheaded again and phenytoin level increased on this reduced dose. She was discharged on 260 mg phenytoin daily. Her serum phenytoin level fell to 18 mcmol/L after 2 months. Her capecitabine was stopped after 2 cycles due to progressive disease. Mechanism of this interaction is postulated to be at the level of the CYP2C9 isoenzyme system. Fluorouracil may competitively inhibit the clearance of phenytoin by the CYP2C9 isoenzyme or may reduce its synthesis 7.
Common questions
Can I take Phenytoin and Fluorouracil Topical together?
Increased phenytoin or fosphenytoin (prodrug of phenytoin) exposure and associated phenytoin or fosphenytoin toxicity Always confirm with your pharmacist or prescriber before making any change.
How serious is the Phenytoin and Fluorouracil Topical interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
Questions for your pharmacist
- Does my dose of Phenytoin or Fluorouracil Topical need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (7)
- Product Information: XELODA(R) oral tablets, capecitabine oral tablets. Genentech USA Inc (per FDA), South San Francisco, CA, 2022. DailyMed
- Product Information: Teysuno oral capsules, tegafur gimeracil oteracil oral capsules. Nordic Group BV (per EMA), Hoofddorp, The Netherlands, 2012.
- Product Information: CEREBYX(R) intravenous injection, fosphenytoin sodium intravenous injection. Pfizer Labs (per FDA), New York, NY, 2015. DailyMed
- Product Information: Dilantin-125(R) oral suspension, phenytoin oral suspension. Parke-Davis (per FDA), New York, NY, 2015. DailyMed
- Product Information: FOSPHENYTOIN SODIUM intravenous and intramuscular injection, fosphenytoin sodium intravenous and intramuscular injection. SAGENT Pharmaceuticals (per Dailymed), Schaumburg, IL, 2024. DailyMed
- Product Information: PHENYTOIN SODIUM intravenous and intramuscular injection, phenytoin sodium intravenous and intramuscular injection. Acella Pharmaceuticals, LLC (per Dailymed), Alpharetta, GA, 2024. DailyMed
- Brickell K, Porter D, & Thompson P: Phenytoin toxicity due to fluoropyrimidines (5FU/capecitabine): three case reports. British Journal of Cancer 2003; 89:615-616. PubMed
Keep reading about Phenytoin
Keep reading about Fluorouracil Topical
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