Capecitabine with Fosphenytoin Interaction Details
Brand Names Associated with Capecitabine
- Capecitabine
- Xeloda®
Brand Names Associated with Fosphenytoin
- Cerebyx®
- Fosphenytoin Injection
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Dec 22, 2023
Interaction Effect
Increased phenytoin exposure and associated phenytoin toxicity
Interaction Summary
Case reports have described phenytoin toxicity during concomitant use of capecitabine or fluorouracil. Coadministration of capecitabine or fluorouracil (the active metabolite of capecitabine) and fosphenytoin or phenytoin may result in elevated phenytoin plasma concentrations , and monitoring of phenytoin levels, with appropriate dosage adjustment, may be warranted . Monitoring should continue if concurrent chemotherapy is discontinued to ensure phenytoin dosage and levels are clinically sufficient .
Severity
Major
Onset
Unspecified
Evidence
Probable
How To Manage Interaction
Carefully monitor phenytoin levels in patients receiving concurrent fluorouracil, or any of its inactive prodrugs, including capecitabine, tegafur, or doxifluridine. Dose reduction of phenytoin may be necessary.
Mechanism Of Interaction
Inhibition of CYP2C9-mediated phenytoin metabolism
Literature Reports
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 .
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 .
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 intravenous 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. Six weeks after starting therapy she was admitted with a 2-day history of an unsteady gate, recurrent falls, weakness, poor balance, and limb ataxia. Her serum phenytoin level was 161 mcmol/L (40-80). Her phenytoin was withheld for 5 days until her serum phenytoin level was under 80 mcmol/L and the dose was reduced to 300 mg daily. She became lightheaded again and her serum phenytoin level increased on this reduced dose (level of 104 mcmol/L). 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. The mechanism of this interaction is postulated to be at the level of the CYP2C9 isoenzyme system. Capecitabine is an orally administered prodrug of fluorouracil. Fluorouracil may competitively inhibit the clearance of phenytoin by the CYP2C9 isoenzyme or may reduce its synthesis .
Capecitabine Overview
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Capecitabine is used in combination with other medications to treat breast cancer that has come back after treatment with other medications. It is also used alone to treat breast cancer that has not improved after treatment with other medications. Capecitabine is also used to treat colon or rectal cancer (cancer that begins in the large intestine) that has gotten worse or spread to other parts of the body. It is also used to prevent colon cancer from spreading in people who have had surgery to remove the tumor. Capecitabine is in a class of medications called antimetabolites. It works by stopping or slowing the growth of cancer cells.
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.