Cyclophosphamide with Fosphenytoin Interaction Details
Brand Names Associated with Cyclophosphamide
- CPM
- CTX
- Cyclophosphamide
- CYT
- Cytoxan®
Brand Names Associated with Fosphenytoin
- Cerebyx®
- Fosphenytoin Injection
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Dec 26, 2023
Interaction Effect
Increased plasma concentrations of the active metabolite of cyclophosphamide and an increased risk of toxicity
Interaction Summary
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 adjustments.
Severity
Major
Onset
Unspecified
Evidence
Probable
How To Manage Interaction
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, the active metabolite, should guide further dosage adjustments.
Mechanism Of Interaction
Induction of CYP2B6-mediated metabolism of cyclophosphamide (prodrug) to its active metabolite
Literature Reports
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 .
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 .
Cyclophosphamide Overview
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Cyclophosphamide is used alone or in combination with other medications to treat Hodgkin's lymphoma (Hodgkin's disease) and non-Hodgkin's lymphoma (types of cancer that begin in a type of white blood cells that normally fights infection); cutaneous T-cell lymphoma (CTCL, a group of cancers of the immune system that first appear as skin rashes); multiple myeloma (a type of cancer of the bone marrow); and certain types of leukemia (cancer of the white blood cells), including chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute myeloid leukemia (AML, ANLL), and acute lymphoblastic leukemia (ALL). It is also used to treat retinoblastoma (cancer in the eye), neuroblastoma (a cancer that begins in nerve cells and occurs mainly in children), ovarian cancer (cancer that begins in the female reproductive organs where eggs are formed), and breast cancer. Cyclophosphamide is also used to treat nephrotic syndrome (a disease that is caused by damage to the kidneys) in children whose disease has not improved, has gotten worse, or has come back after taking other medications or in children who experienced intolerable side effects with other medications. Cyclophosphamide is in a class of medications called alkylating agents. When cyclophosphamide is used to treat cancer, it works by slowing or stopping the growth of cancer cells in your body. When cyclophosphamide is used to treat nephrotic syndrome, it works by suppressing your body's immune system.
Fosphenytoin Overview
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Fosphenytoin injection is used to treat primary generalized tonic-clonic seizures (formerly known as a grand mal seizure; seizure that involves the entire body) and to treat and prevent seizures that may begin during or after surgery to the brain or nervous system. Fosphenytoin injection may also be used to control certain type of seizures in people who cannot take oral phenytoin. Fosphenytoin is in a class of medications called anticonvulsants. It works by decreasing abnormal electrical activity in the brain.
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Definitions
Severity Categories
Contraindicated
These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.
Major
This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.
Moderate
This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.
Minor
While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.
Onset
Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.
Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.
Evidence
Level of documentation of the interaction.
Established: The interaction is documented and substantiated in peer-reviewed medical literature.
Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.
How To Manage The Interaction
Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.
It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.
Mechanism Of Interaction
The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.
Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.
Where Does Our Information Come From?
Information for our drug interactions is compiled from several drug compendia, including:
The prescribing information for each drug, as published on DailyMED, is also used.
Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.
The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.