Folic Acid with Fosphenytoin Interaction Details
Brand Names Associated with Fosphenytoin
- Cerebyx®
- Fosphenytoin Injection
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Nov 13, 2023
Interaction Effect
Decreased folic acid serum levels; decreased phenytoin effectiveness
Interaction Summary
Concurrent use of folic acid and phenytoin has resulted in increased seizure frequency in some epileptic patients on phenytoin therapy who received supplemental oral folic acid. Decreased phenytoin levels were observed in folate-deficient patients who received 5 mg or 15 mg of folic acid daily. Subnormal folate levels frequently develop in patients receiving long-term phenytoin therapy, but progression to megaloblastic anemia occurs in less than 1% of patients .
Severity
Moderate
Onset
Delayed
Evidence
Probable
How To Manage Interaction
The concomitant use of folic acid and phenytoin may result in decreased folic acid or phenytoin blood levels. If folic acid is added to phenytoin therapy, monitor patients for decreased seizure control.
Mechanism Of Interaction
Decreased folate absorption; increased phenytoin metabolism
Literature Reports
A) Subnormal serum folate concentrations occur in 27% to 91% of patients receiving long-term phenytoin . Progression to megaloblastic anemia occurs in less than 1% of patients , although macrocytosis is common . Reduced folate concentrations in RBCs and cerebrospinal fluid (CSF) have also been identified in patients receiving chronic phenytoin therapy . The development of subnormal folate levels in this patient population does not appear related to dose, duration of therapy, or serum levels.
B) Several studies have addressed the effect of folic acid supplementation on the serum concentrations of phenytoin. In 5 subjects receiving phenytoin 300 mg daily, blood phenytoin levels were measured for 10 days, then patients were started on folic acid 10 mg daily for 15 days. Phenytoin blood levels decreased by 15% to 45% within 10 days . A similar study found a mean decrease in serum phenytoin levels of 16% . Two studies reported significant decreases in phenytoin blood levels in a total of 62 epileptic patients receiving folic acid 5 to 15 mg daily. One study showed 11 of 12 patients had decreases in serum phenytoin levels up to 20%, with one patient experiencing a drop of 50% . The other report described a patient receiving folic acid 5 mg daily who had increased frequency and severity of seizures after 10 days of therapy . Case studies have also described decreased phenytoin concentrations and subsequent loss of seizure control as a result of folic acid supplementation . Some uncontrolled studies have also reported a loss of seizure control . However, numerous large controlled studies, mostly double-blind, have found no significant difference in mean seizure frequency when a group of folate-deficient epileptic patients treated with folic acid was compared with a similar group receiving placebo .
C) It may be possible that both indirect effects upon phenytoin's pharmacokinetic disposition and direct effects on seizure frequency are involved in folate's interaction with phenytoin. Several studies indicate that folic acid supplementation increases phenytoin liver metabolism; two studies suggest increased phenytoin parahydroxylation , and another suggests increased O-methylation of the catechol metabolite . One study concluded that folic acid does not stimulate phenytoin metabolism, but that change in the rates of different elimination pathways was responsible . Evidence of a direct effect includes animal data which demonstrates strong seizure-evoking potential of folic acid, especially when injected directly into the third ventricle of the brain . Although several controlled studies with folate showed no significant effect on seizure frequency in patients controlled with phenytoin, one author theorized that the studies may not have been conducted over a sufficient period of time, since cerebrospinal fluid (CSF) folate concentrations may take several months to rise . However, this does not explain why short-term folate therapy can markedly increase seizure frequency in some patients previously stabilized on phenytoin.
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.