In some patients plasma levels of phenytoin are slightly raisedby topiramate, and topiramate plasma levels may be reduced byphenytoin.
Topiramate,titrated to a maximum of 400mg twice daily, was given to 12 epileptic patients taking phenytoin 260 to 600mg daily. When maximum tolerated dose of topiramate was reached, phenytoin dose was then reduced, and in some cases phenytoin was subsequently discontinued. Topiramate clearance was assessed in 2 patients and was found to be increased two to threefold by phenytoin (See reference number 1). Similarly,a population pharmacokinetic study reported that patients taking phenytoin and topiramate had 50 % lower morning topiramate levels than patients not taking enzyme-inducing antiepileptics (See reference number 2).
In first study above, 3 of 12 patients had a decrease in phenytoin clearance and an increase of 25 to 55 % in AUC of phenytoin when taking topiramate: other 9 had no changes (See reference number 1). This slight increase is said not to be clinically significant based on analyses from six add-on studies (See reference number 3).
An in vitro study using human liver microsomes found that topiramate does not inhibit most hepatic cytochrome P450 isoenzymes,except for CYP2C19 at high concentrations (See reference number 1). This isoenzyme plays a minor role in phenytoin metabolism,but it has been suggested this may become important at high doses of topiramate in patients who are poor CYP2C9 metabolisers,(See reference number 1) (see genetic factors in drug metabolism, , for more information). Phenytoin appears to induce metabolism of topiramate.
The interaction between topiramate and phenytoin appears to be established,and topiramate dose adjustments may be required if phenytoin is added or discontinued. No reduction in phenytoin dosage seems necessary in majority of patients, but be aware that a few patients may have increased phenytoin levels, particularly at high topiramate doses. Monitor phenytoin levels.
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