Cyclophosphamide Injection and Fosphenytoin: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Fosphenytoin
Cyclophosphamide Injection
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 plasma concentrations of the active metabolite of cyclophosphamide and an increased risk of toxicity
Interaction Deep Dive
The concomitant use of cyclophosphamide (prodrug, primarily a CYP2B6 substrate) and phenytoin, a CYP2B6 inducer, may result in increased plasma concentrations of 4-hydroxycyclophosphamide, the active metabolite of cyclophosphamide, and an increased risk of toxicity. In a case report, the concomitant use of cyclophosphamide and phenytoin resulted in a 51% increase in the AUC and a 600% increase in Cmax of 4-hydroxycyclophosphamide compared with 4-hydroxycyclophosphamide exposure prior to coadministration with phenytoin. Coadministration of cyclophosphamide and phenytoin should be avoided if possible and an alternative antiepileptic that does not have hepatic enzyme induction capabilities should be selected. If coadministration is necessary, the starting dose of cyclophosphamide should be reduced and monitoring of 4-hydroxycyclophosphamide levels should guide further cyclophosphamide dosage adjustments1.
Why it happens (mechanism)
Induction of CYP2B6-mediated metabolism of cyclophosphamide (prodrug) to its active metabolite
Literature reports
2 reports — tap to read
a) The concomitant use of cyclophosphamide and phenytoin resulted in a 51% increase in the AUC (144 vs 217 mcmol/L/hr) of 4-hydroxycyclophosphamide, the active metabolite of cyclophosphamide, and a 600% increase in Cmax (1090 vs 6550 nanograms/milliliter) compared with 4-hydroxycyclophosphamide exposure prior to coadministration with phenytoin in a case report of a 42-year-old man with relapsing non-seminomous testis cancer. The elimination of 4-hydroxycyclophosphamide was increased, because elimination of the metabolite is a formation-rate limiting event. The patient received phenytoin 150 mg orally twice daily 5 days prior to the second cycle of cyclophosphamide. The cyclophosphamide dose was subsequently reduced from 2835 mg/day during cycle 1 to 1500 mg/day in cycle 2, which resulted in 4-hydroxycyclophosphamide plasma levels within the therapeutic margin. There was no toxicity observed following the cyclophosphamide dose reduction during the second cycle 1.
b) In a pharmacokinetic study including 3 patients who received concomitant cyclophosphamide and phenytoin, the formation of 4-hydroxycyclophosphamide, the active metabolite of cyclophosphamide, was increased from 74% to 86% for R-cyclophosphamide and from 78% to 90% for S-cyclophosphamide. There was a corresponding decrease of 40% in the Cmax of prodrug cyclophosphamide 2.
Common questions
Can I take Cyclophosphamide Injection and Fosphenytoin together?
Increased plasma concentrations of the active metabolite of cyclophosphamide and an increased risk of toxicity Always confirm with your pharmacist or prescriber before making any change.
How serious is the Cyclophosphamide Injection and Fosphenytoin 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 Cyclophosphamide Injection or Fosphenytoin 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 (2)
- de Jonge ME, Huitema AD, van Dam SM, et al: Significant induction of cyclophosphamide and thiotepa metabolism by phenytoin. Cancer Chemother Pharmacol 2005; 55(5):507-510. PubMed
- Williams ML, Wainer IW, Embree L, et al: Enantioselective induction of cyclophosphamide metabolism by phenytoin. Chirality 1999; 11(7):569-574. DOI
Keep reading about Fosphenytoin
Keep reading about Cyclophosphamide Injection
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