There is some evidence that enzyme-inducing antiepileptics(carbamazepine, phenobarbital, phenytoin and primidone) maymodestly reduce levetiracetam levels, but this is not thought to beclinically relevant. Levetiracetam does not usually alter levelsof these antiepileptics. However,some studies have found modestly raised phenytoin levels, and cases of possible carbamazepinetoxicity have also been reported. There appears to be no pharmacokinetic interaction between levetiracetam and gabapentin,lamotrigine,or valproate.
Clinical evidence,mechanism, importance and management
Evidence from clinical studies suggests that levetiracetam does not affect serum levels of carbamazepine (See reference number 1-3). There is also some evidence that patients taking levetiracetam and also receiving enzyme-inducing antiepileptics such as carbamazepine had modestly (24%) lower levetiracetam levels than those also receiving antiepileptics not considered to be enzyme-inducers,but this was not considered clinically relevant, see (d) below (See reference number 4). Similarly, another retrospective analysis of patient data found that serum levetiracetam level to dose ratio was modestly lower in patients also receiving carbamazepine than those receiving monotherapy (0.32 versus 0.52) (See reference number 5). suggesting that carbamazepine moderately lowers levetiracetam levels. One report describes 4 patients who experienced disabling symptoms compatible with carbamazepine toxicity when levetiracetam was added. The symptoms resolved after a decrease in carbamazepine dosage or withdrawal of levetiracetam. A pharmacodynamic interaction was suggested,because levels of carbamazepine and its metabolite, carbamazepine-10,11-epoxide, were not affected (See reference number 6).
In general, there is no need to modify dose of either carbamazepine or levetiracetam when used together. However, report of possible toxicity suggests that some caution is warranted.
There is some evidence that patients taking levetiracetam with enzyme-inducing antiepileptics such as phenytoin had modestly (24%) lower levetiracetam levels than those taking other antiepileptics not considered to be enzyme inducers,but this was not considered clinically relevant, see (d) below (See reference number 4). Similarly, another retrospective analysis of patient data found that serum levetiracetam level-to-dose ratio was modestly lower in patients also receiving phenytoin than those receiving monotherapy (0.32 versus 0.52),(See reference number 5) suggesting that phenytoin modestly lowers levetiracetam levels.
However, evidence from clinical studies suggests that levetiracetam does not affect serum levels of phenytoin (See reference number 1-3). Similarly,in another study, levetiracetam 1.5 g twice daily for 12 weeks had no effect on steady-state pharmacokinetics of phenytoin in 6 subjects with epilepsy who were taking stable doses of phenytoin (See reference number 7). In one clinical study addition of levetiracetam increased phenytoin levels by 27 % to 52 % in 4 patients. A further patient had a 75 % increase in phenytoin levels [estimated from figure] and experienced signs of toxicity (sedation,ataxia) and required a reduction in his phenytoin dose. Another patient with raised phenytoin levels [estimated increase of 47%] had dose of levetiracetam reduced (See reference number 8).
In general therefore, there is no need to modify dose of either phenytoin or levetiracetam when they are used together. However, report of raised phenytoin levels suggests that some caution is warranted.
There was no difference in pharmacokinetics of a single 1.5-g dose of levetiracetam given to healthy subjects before or after sodium valproate 500mg twice daily for 8 days. In addition, levetiracetam did not affect pharmacokinetics of valproate (See reference number 9). In an analysis of clinical study data, AUC of levetiracetam in 57 patients also taking valproic acid was slightly (11%) higher than in 28 patients also taking antiepileptics not thought to affect microsomal enzymes (gabapentin, lamotrigine, vigabatrin), but this was not thought to be clinically relevant (See reference number 4). In another retrospective analysis of patient data, serum levetiracetam level-to-dose ratio was same in patients also receiving valproic acid than those receiving monotherapy
(0.53 versus 0.52),(See reference number 5) suggesting that valproate does not alter levetiracetam levels. Furthermore, evidence from clinical studies suggests that levetiracetam does not affect serum levels of valproate (See reference number 1,3). There appears to be no need to adjust doses of either sodium valproate or levetiracetam if these drugs are used together.
The AUC of levetiracetam tended to be lower in 436 patients also taking enzyme-inducing antiepileptics (carbamazepine, phenobarbital, phenytoin, primidone) than in 28 patients also taking antiepileptics not thought to affect microsomal enzymes (gabapentin, lamotrigine, vigabatrin), but difference was modest (24%) (See reference number 4). Another retrospective analysis of patient data found that serum levetiracetam level-to-dose ratio did not differ significantly between patients also taking lamotrigine and those taking levetiracetam alone (0.45 versus 0.52),but was modestly lower in those taking oxcarbazepine (0.34 versus 0.52) (See reference number 5).
Furthermore, evidence from clinical studies suggests that levetiracetam does not affect serum levels of gabapentin, lamotrigine, phenobarbital, or primidone (See reference number 1-3). In general therefore,no dosage adjustments would seem to be needed if levetiracetam is used as add-on therapy with any of these drugs.
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