Important Drug Interactions for the Seizure Drug Phenytoin

Patients taking the commonly prescribed epilepsy drug phenytoin (DILANTIN, PHENYTEK) should be aware that it has clinically important interactions with many other prescription and over-the-counter medications.

Introduced in the 1930s, phenytoin is one of the oldest epilepsy drugs.[1] It was first approved by the Food and Drug Administration in 1953[2] and is used as a first-line agent to treat two types of seizures: generalized (tonic-clonic or grand mal) seizures and partial (focal) seizures.[3]

Drugs that affect phenytoin levels[4],[5]

Like many drugs, phenytoin is metabolized (broken down or chemically modified) by substances in the liver called enzymes. Phenytoin is particularly susceptible to interactions with drugs that inhibit the enzymes involved in the breakdown of phenytoin, which can lead to significantly increased blood levels of the drug and phenytoin toxicity.

Table 1, below, provides examples of drugs that may increase phenytoin blood levels, potentially resulting in phenytoin toxicity. These include antibiotics, antidepressants, antifungal drugs, other epilepsy drugs and medications for decreasing stomach acid. Signs of phenytoin toxicity include loss of muscle coordination, involuntary repetitive eye movements, slurred speech, sleepiness and confusion.

Other drugs can enhance the breakdown of phenytoin or block its absorption from the gut, potentially resulting in subtherapeutic levels of phenytoin and inadequate seizure control (see Table 2, below, for examples). Such drugs include antacids, antiviral drugs, and the benzodiazepine diazepam (VALIUM).

Finally, there are other epilepsy drugs that have unpredictable effects on phenytoin levels. Using these drugs — which include carbamazepine (CARBATROL, EPITOL, EQUETRO, TEGRETOL, TERIL), phenobarbital (LUMINAL, SOLFOTON) and valproic acid (DEPAKENE) — with phenytoin may result in increased or decreased levels of phenytoin.

Because of the potential harm that may result from these interactions, phenytoin blood levels should be monitored when a patient starts or stops any drug that may alter phenytoin levels.

Table 1: Examples of Oral Drugs That May Increase Phenytoin Levels

*Designated as Limited Use
**Designated as Do Not Use
***Designated as Do Not Use Except for Serious Fungal Infections
†Over-the-counter product

Table 2: Examples of Oral Drugs That May Decrease Phenytoin Levels

*Designated as Limited Use
**Designated as Do Not Use
†Over-the-counter product

Other drugs affected by phenytoin[6],[7]

Phenytoin itself can interfere with the effectiveness of many other drugs, most commonly by decreasing the blood levels of the interacting drugs. The drugs that phenytoin may affect include antifungal drugs, other epilepsy drugs, calcium channel blockers for hypertension, cholesterol-lowering statins and oral contraceptives (see Table 3, below, for examples). Notably, many of the drugs that affect phenytoin levels are also simultaneously affected by phenytoin.
 

Table 3: Examples of Oral Drugs That May Be Affected by Phenytoin

*Designated as Limited Use
**Designated as Do Not Use
***Designated as Do Not Use Except for Serious Fungal Infections

What You Can Do

If you need treatment with phenytoin to control seizures, review all of your other medications with your doctor to assess for potentially significant drug interactions. Be aware that other drugs not listed in this article also may have dangerous interactions with phenytoin. If you are taking phenytoin, you may need to undergo blood tests to monitor phenytoin levels after starting or stopping a new drug that may interact with phenytoin.
 

References

[1] Schachter SC. Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects. UpToDate. May 2019.

[2] Pfizer. Label: phenytoin (DILANTIN). October 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/084349s085lbl.pdf . Accessed July 3, 2019.

[3] Schachter SC. Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects. UpToDate. May 2019.

[4] Pfizer. Label: phenytoin (DILANTIN). October 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/084349s085lbl.pdf. Accessed July 3, 2019.

[5] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Accessed June 15, 2019.

[6] Pfizer. Label: phenytoin (DILANTIN). October 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/084349s085lbl.pdf. Accessed June 13, 2019.

[7] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Accessed June 15, 2019.