Men and women receiving some antiepileptic drugs (AEDs) are at risk for low levels of serum and red blood cell folic acid (1):
- serum and red blood cell folate are reduced in up to 90% of patients receiving phenytoin (PHT), carbamazepine (CBZ), or barbiturates
- AEDs that do not induce cytochrome P450 enzymes are not associated with low levels of folic acid
- lamotrigine (LTG), an AED that has weak folate properties in vitro, had no effects on serum or red blood cell folate in 14 patients on short-term treatment and in an additional 14 patients who had been treated for up to 5 years
A review describes considerations when using the combination of phenytoin and folic acid (2):
Benefits of using the combination
- may be necessary for people to take both phenytoin and folic acid.
Folic acid may be required:
- to treat folate deficiency
- for women who are pregnant or planning pregnancy to reduce the risk of congenital abnormalities
Long-term treatment with phenytoin can reduce folate levels (2)
- folate deficiency in a patient taking phenytoin may be an adverse effect of phenytoin or due to other causes
Risks of using the combination of phenytoin and folic acid
- treatment with folic acid can reduce phenytoin levels, which can lead to loss of seizure control (2)
Managing the interaction
- if folic acid is initiated for a patient established on phenytoin, monitor phenytoin blood levels
- phenytoin dosage should be adjusted accordingly.
- refer to the patient’s neurologist if there are concerns about managing seizure control or the interaction
- consult information about phenytoin monitoring
Measure baseline phenytoin levels
- ideally measure baseline phenytoin levels, before initiating folic acid
- baseline level can be compared with repeat levels to determine if a dose adjustment is necessary
- serum range of (total) phenytoin is generally 10 to 20 milligrams/L (2)
- note though that some people obtain seizure control at lower blood phenytoin levels.
Adjust phenytoin dose if necessary
- take a risk versus benefit approach, and involve patients when considering whether to adjust the phenytoin dose (2)
- for patients managed with lower phenytoin blood levels consider the risk of loss of seizure control versus exposure to increased adverse effects when considering pre-emptive dose increases.
Repeat phenytoin levels
- phenytoin takes 7 to 10 days to reach steady-state
- take phenytoin levels at least 7 days after starting folic acid and after any dose changes
- use repeat levels to guide requirements for phenytoin dose adjustments.
- adjust monitoring frequency based on individual patient characteristics. Patients in whom levels and seizure control are stable will require less frequent monitoring.
- for stable patients requiring long-term folic acid, phenytoin levels should be monitored at 3 to 12 month intervals
Managing dose adjustments
- phenytoin pharmacokinetics are non-linear
- small alterations in dose may lead to significant changes in blood levels, resulting in dose-related toxicity or loss of seizure control
- if phenytoin dose adjustment is required following the addition of folic acid, increase the dose in increments of 25mg. Wait at least seven days after dose adjustment before re-measuring phenytoin blood levels.
Stopping folic acid
- if the phenytoin dose was increased during folic acid therapy, consider dose reduction once folic acid is discontinued
- dose reduction should be gradual and be guided by phenytoin levels and the presence of any phenytoin-related adverse effects
- the aim is to prevent dose-related toxicity from increased levels whilst minimising impact on seizure control.
- take a phenytoin level at least 7 days after phenytoin dose adjustment
- use this level, presence of adverse effects and seizure control to guide requirements for further dose adjustments or drug level monitoring
Once folate levels are in range, the summary of product characteristics for phenytoin recommends monitoring folate levels at least once every 6 months
For full details see NHS Specialist Pharmact Service (April 12th 2024). Using folic acid with phenytoin
Reference:
- Morrell MJ. Folic Acid and Epilepsy. Epilepsy Curr. 2002 Mar;2(2):31-34. doi: 10.1111/j.1535-7597.2002.00017.x. PMID: 15309159; PMCID: PMC320966.