Brands, Medical Use, Clinical Data
- Nootropic Agents
Brands / Synonyms
Keppra; Keppra XR; Levetiracetam; Levetiracetam [INN]; Levetiracetamum [INN-Latin]
Used as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy.
Mechanism of Action
The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. The antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures. Levetiracetam did not inhibit single seizures induced by maximal stimulation with electrical current or different chemoconvulsants and showed only minimal activity in submaximal stimulation and in threshold tests. Protection was observed, however, against secondarily generalized activity from focal seizures induced by pilocarpine and kainic acid, two chemoconvulsants that induce seizures that mimic some features of human complex partial seizures with secondary generalization. Levetiracetam also displayed inhibitory properties in the kindling model in rats, another model of human complex partial seizures, both during kindling development and in the fully kindled state. The predictive value of these animal models for specific types of human epilepsy is uncertain.
Rapidly and almost completely absorbed after oral administration (99%). Peak plasma concentrations occurring in about an hour following oral administration in fasted subjects.
Side effects include aggression, agitation, coma, drowsiness, reduced consciousness, slowed breathing
Biotrnasformation / Drug Metabolism
The major metabolic pathway of levetiracetam (24% of dose) is an enzymatic hydrolysis of the acetamide group. No CYP450 metabolism detected.
This product should not be administered to patients who have previously exhibited hypersensitivity to
levetiracetam or any of the inactive ingredients in Keppra® tablets or oral solution.
in vitro data on metabolic interactions indicate that Keppra® is unlikely to produce, or be subject to,
pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above cmax
levels achieved within the therapeutic dose range, are neither inhibitors of nor high affinity substrates for human
liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not
affect the in vitro glucuronidation of valproic acid.
Levetiracetam circulates largely unbound (<10% bound) to plasma proteins; clinically significant interactions
with other drugs through competition for protein binding sites are therefore unlikely.
Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic studies (phenytoin, valproate,
oral contraceptive, digoxin, warfarin, probenecid) and through pharmacokinetic screening in the placebo-controlled
clinical studies in epilepsy patients.
Drug-Drug Interactions Between Keppra® And Other Antiepileptic Drugs (AEDs)
Keppra® (3000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with
refractory epilepsy. Pharmacokinetics of levetiracetam were also not affected by phenytoin.
Keppra® (1500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate
500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary
excretion. There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057.
Potential drug interactions between Keppra® and other AEDs (carbamazepine, gabapentin, lamotrigine,
phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of
levetiracetam and these AEDs during placebo-controlled clinical studies. These data indicate that levetiracetam does
not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of
Effect of AEDs in Pediatric Patients
There was about a 22% increase of apparent total body clearance of levetiracetam when it was co-administered with
enzyme-inducing AEDs. Dose adjustment is not recommended.Levetiracetam had no effect on plasma concentrations of
carbamazepine, valproate, topiramate, or lamotrigine.
Other Drug Interactions
Keppra® (500 mg twice daily) did not influence the pharmacokinetics of an oral contraceptive containing 0.03
mg ethinyl estradiol and 0.15 mg levonorgestrel, or of the luteinizing hormone and progesterone levels, indicating
that impairment of contraceptive efficacy is unlikely.
Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam.
Keppra® (1000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin
given as a 0.25 mg dose every day. Coadministration of digoxin did not influence the pharmacokinetics of
Keppra® (1000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was
not affected by levetiracetam. Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam.
Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not
change the pharmacokinetics of levetiracetam 1000 mg twice daily. Cssmax of the metabolite, ucb L057, was
approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine
remained the same. Renal clearance of ucb L057 in the presence of probenecid decreased 60%, probably related to
competitive inhibition of tubular secretion of ucb L057. The effect of Keppra® on probenecid was not studied.