ed adverse effects were noted. In another case series including 11 mother-infant pairs, levetiracetam was excreted into breast milk at a concentration similar to that in maternal plasma; the mean milk:plasma ratio was 1.05 (range 0.78—1.55). Assuming a daily milk intake of 150 ml/kg/day, the infant dose was estimated to be approximately 2.4 mg/kg/day. Although no safe dosage range has been established in the neonatal population, initial doses of 14 mg/kg/day PO are FDA approved for patients as young as one month of age (see Dosage). NOTE: In this study, milk concentrations were single, morning trough concentrations collected between day 4 and 23 after delivery; therefore, total infant exposure over a 24-hour period may differ from this estimate. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated seizure disorder. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
MECHANISM OF ACTION
Mechanism of Action: The precise mechanism of action of levetiracetam is not known. Its antiepileptic effect does not appear to involve known mechanisms relating to inhibitory and excitatory neurotransmission. In animal models, levetiracetam did not inhibit single seizures induced by maximal stimulation with electrical current or different chemoconvulsants. It also showed only minimal activity in submaximal stimulation in threshold tests. Levetiracetam did, however, protect 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, which is 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.In vitro studies show that levetiracetam, up to 1700 mcg/ml, did not result in significant ligand displacement at known receptor binding sites. Second messenger systems, ion channel proteins, glutamate receptor-mediated neurotransmission, muscimol-induced chloride flux, and gamma-aminobutyric acid (GABA)-transaminase and glutamate decarboxylase activities were unaffected by levetiracetam. Benzodiazepine receptor antagonists (e.g., flumazenil) had no effect on levetiracetam's protection against seizures. Conversely, a stereoselective binding site for the drug has been demonstrated to exist exclusively in synaptic plasma membranes in the CNS, but not in peripheral tissue.In vitro and in vivo recordings of epileptiform activity from the hippocampus have shown that levetiracetam inhibits burst firing without affecting normal neuronal excitability. This suggests that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.
PHARMACOKINETICS
Levetiracetam is administered orally and intravenously. Protein binding is less than 10%, making competition for protein binding sites and clinically significant interactions with other drugs unlikely. Volume of distribution (Vd) is 0.7 L/kg. Levetiracetam is not extensively metabolized. Approximately 24% of the adminis |
