Benefits of using the combination

It 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. Folate deficiency in a patient taking phenytoin may be an adverse effect of phenytoin or due to other causes.

Managing folate deficiency

The recommended dose of folic acid to treat folate deficiency is 5mg once daily for four months. Up to 15mg daily may be necessary for patients with malabsorption states.

Four months’ treatment is generally sufficient to induce haematological remission and replenish body stores. Check full blood count and reticulocyte count on completion of folic acid treatment to confirm response.

In some people, folic acid may need to be continued long-term. If low folate recurs after folic acid supplementation is stopped, ongoing replacement should be considered.

Prevention of neural tube defects

Women require additional folate during pregnancy to support the development of the baby. Low folate levels in the mother are associated with neural tube defects such as spina bifida.

As phenytoin can reduce folate levels a higher dose of 5mg folic acid is recommended for all pregnant women, and those planning pregnancy.

Ideally, this should be taken from three months before conception and until week 12 of pregnancy.

Best Use of Medicines in Pregnancy (BUMPS) can be accessed for further information regarding the use of folic acid in pregnancy.

Risks of using the combination

Treatment with folic acid can reduce phenytoin levels, which can lead to loss of seizure control.

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

See our medicines monitoring tool for general information about Phenytoin monitoring

Measure baseline phenytoin levels

Ideally measure baseline phenytoin levels, before initiating folic acid. The baseline level can be compared with repeat levels to determine if a dose adjustment is necessary.

The serum range of (total) phenytoin is generally 10 to 20 milligrams/L. However, 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.

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.

Counselling

Patients taking phenytoin should be advised on the following when starting treatment with folic acid:

• folic acid can reduce the effectiveness of phenytoin
• blood phenytoin levels will be monitored and the phenytoin dose may be adjusted if necessary
• to report any change in seizure frequency to their doctor

If the dose of phenytoin was increased while taking folic acid, it may need to be reduced when folic acid is stopped. Patients should be alert for signs of phenytoin toxicity such as vomiting and lethargy and tell their doctor if they occur.

Women of child-bearing potential

Women taking phenytoin require a higher daily dose of folic acid supplementation before conception and during pregnancy.

Women taking phenytoin considering pregnancy should be seen by a specialist, to consider the risks and benefits of their current antiseizure medication regimen. A full review and dose adjustment may be required.

Further information

The following SPS resources are available for further information:

Drug interactions: resources to support answering questions to common resources for checking medicine interactions.

Understanding drug interactions discusses different mechanisms of drug interactions, including pharmacodynamics and pharmacokinetic interactions.

Primary care healthcare professionals in England can seek further advice from our Medicines Advice service if the information is not available on the SPS website, or if the clinical scenario is complex.

Bibliography

Full referencing is available on request.