====== Levetiracetam ====== {{rss>https://pubmed.ncbi.nlm.nih.gov/rss/search/1NosRw4HLZN0ZT_5PLUarcjuaZMRDT_G0-RQLOzYEx2ce4dsQp/?limit=15&utm_campaign=pubmed-2&fc=20230930162021}} Since [[2000]], [[Levetiracetam]] (LEV) has been marketed around the world as an [[antiepileptic Drug]] under the brand name [[Keppra]]. ===== Indications ===== It is used for partial-onset, myoclonic, or tonic-clonic seizures. It is taken by mouth as an immediate or extended-release formulation or by injection into a vein. No identified drug-drug interactions. Less than 10% protein bound. Linear pharmacokinetics, no level ---- Adjunctive therapy for partial-onset Sz with secondary generalization in patients 4 years of age and older. Myoclonic seizures (juvenile myoclonic epilepsy). Generalized tonic-clonic. monitoring needed. ---- [[Levetiracetam for posttraumatic epileptic seizure prophylaxis]] ---- [[Brain tumor-related epilepsy treatment]]. ---- see [[Levetiracetam for hemifacial spasm]]. ===== Dosing ===== ℞ start with 500mg PO BID. Increment by 1000 mg/d q 2 weeks PRN to a maximum of 3000 mg/d. Keppra XR: the same dose of levetiracetam can be converted to Keppra XR for q d dosing. IV: 500–1500mg diluted in 100 ml of diluent (LR, D5W, normal saline) infused over 15 minutes BID. Supplied: 250, 500, 750 & 1000mg scored film-coated tabs; 100 mg/ml oral solution. Keppra XR (extended-release) 500 mg. IV: 1 vial (5 ml) contains 500 mg. ===== Pharmacokinetics ===== Absorption: Route of Administration: Levetiracetam is available in oral tablet and oral solution forms. It is well-absorbed when taken orally, with an oral bioavailability of approximately 100%. Food Effects: Levetiracetam can be taken with or without food, as food does not significantly affect its absorption. Distribution: Volume of Distribution: Levetiracetam has a relatively small volume of distribution, indicating that it is largely confined to the bloodstream and does not extensively distribute into tissues. Protein Binding: Levetiracetam exhibits low plasma protein binding, typically less than 10%. This means that a significant portion of the drug remains in its free, active form in the bloodstream. Metabolism: Metabolism: Levetiracetam does not undergo significant metabolism in the liver. It is primarily excreted from the body unchanged. Elimination: Half-Life: The half-life of levetiracetam in adults is approximately 6-8 hours. In children, it may be shorter, around 4-6 hours. Renal Clearance: The primary route of elimination for levetiracetam is through the kidneys. It is primarily excreted unchanged in the urine. Renal Impairment: Individuals with impaired renal function may require dosage adjustments because levetiracetam is primarily eliminated by the kidneys. Dose adjustments are typically made based on creatinine clearance. Special Populations: Pediatric Patients: The pharmacokinetics of levetiracetam in children may differ from adults, primarily due to differences in clearance. Dosing in pediatric patients is often adjusted based on age and weight. Elderly Patients: Although levetiracetam is generally well-tolerated in elderly patients, dose adjustments may be necessary if there is impaired renal function due to age. Drug Interactions: Levetiracetam is known for having a low potential for drug interactions. It is less likely to interact with other medications compared to some other antiepileptic drugs. However, interactions are still possible, so it's essential to discuss all medications with a healthcare provider. Therapeutic Drug Monitoring: Unlike some antiepileptic drugs, routine therapeutic drug monitoring (TDM) of levetiracetam is not typically necessary. The drug's linear pharmacokinetics and predictable absorption make it easier to manage without the need for regular blood level monitoring. Overall, levetiracetam's pharmacokinetics make it a convenient and well-tolerated choice for the treatment of epilepsy. Its minimal metabolism, low protein binding, and renal elimination contribute to its predictable and consistent pharmacokinetic profile. However, individual patient factors, such as renal function and age, should be considered when determining the appropriate dosage to achieve optimal seizure control. It's crucial for individuals taking levetiracetam to follow their healthcare provider's dosing instructions and attend regular check-ups to monitor their response to the medication. ---- ===== Mechanism of action ===== Its novel [[mechanism of action]] is the modulation of synaptic [[neurotransmitter]] release through binding to the synaptic vesicle protein [[SV2A]] in the brain. ---- Mechanistically, LEV inhibited the [[JAK2]]-[[STAT3]] signaling pathway and reduced neuronal injury around the hematoma and ameliorated [[brain edema]], all of which promoted recovery of nerve function after hemorrhage ((Xiong J, Zhou H, Lu D, Wang Z, Liu H, Sun Y, Xu J, Feng Y, Xing A. Levetiracetam Reduces Early Inflammatory Response After Experimental Intracerebral Hemorrhage by Regulating the Janus Kinase 2 (JAK2)-Signal Transducer and Activator of Transcription 3 (STAT3) Signaling Pathway. Med Sci Monit. 2020 Apr 14;26:e922741. doi: 10.12659/MSM.922741. PubMed PMID: 32289810. )). ---- Intravenous levetiracetam seems to be an effective, safe antiepileptic drug in hospitalised patients, and especially so in those who present an associated comorbidity and/or who are on multiple drug therapy ((Giner-Bernabeu JC, Hernández-Rubio L, Sempere AP, Bosacoma-Ros N, Berenguer-Ruiz L, Lezcano-Rodas M, Martínez-Lazcano T, Mira-Berenguer F, Baño E, Abarca-Olivas J, Duart M, Asensio-Asensio M. [The use of intravenous levetiracetam in a general hospital]. Rev Neurol. 2009 Nov 16-30;49(10):517-9. Spanish. PubMed PMID: 19859874. )) Levetiracetam (LEV) is the most potent [[O6 methylguanine DNA methyltransferase]] (MGMT)inhibitor among several [[antiepileptic drug]]s (AEDs) with diverse MGMT regulatory actions. In vitro, when used at concentrations within the human therapeutic range for seizure prophylaxis, LEV decreases MGMT protein and mRNA expression levels. Chromatin immunoprecipitation analysis reveals that LEV enhances p53 binding on the MGMT promoter by recruiting the mSin3A/histone deacetylase 1 (HDAC1) corepressor complex. However, LEV does not exert any MGMT inhibitory activity when the expression of either p53, mSin3A, or HDAC1 is abrogated. LEV inhibits malignant glioma cell proliferation and increases glioma cell sensitivity to the monofunctional alkylating agent temozolomide. In 4 newly diagnosed patients who had 2 craniotomies 7-14 days apart, prior to the initiation of any tumor-specific treatment, samples obtained before and after LEV treatment showed the inhibition of MGMT expression. This results suggest that the choice of AED in patients with malignant gliomas may have an unrecognized impact in clinical practice and research trial design ((Bobustuc GC, Baker CH, Limaye A, Jenkins WD, Pearl G, Avgeropoulos NG, Konduri SD. Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide. Neuro Oncol. 2010 Sep;12(9):917-27. doi: 10.1093/neuonc/noq044. PubMed PMID: 20525765; PubMed Central PMCID: PMC2940696. )). ---- Levetiracetam LEV may provide a survival benefit in patients with glioblastoma who receive temozolomide-based chemotherapy. A prospective randomized study may be indicated ((Kim YH, Kim T, Joo JD, Han JH, Kim YJ, Kim IA, Yun CH, Kim CY. Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme. Cancer. 2015 Sep 1;121(17):2926-32. doi: 10.1002/cncr.29439. PubMed PMID: 25975354. )) Levetiracetam appears effective and safe for seizure prevention in patients undergoing brain tumor resection and who are at significantly higher risk of developing post-operative seizures. These findings warrant confirmation in a prospective randomized trial ((Gokhale S, Khan SA, Agrawal A, Friedman AH, McDonagh DL. Levetiracetam seizure prophylaxis in craniotomy patients at high risk for postoperative seizures. Asian J Neurosurg. 2013 Oct;8(4):169-73. doi: 10.4103/1793-5482.125658. PubMed PMID: 24550999; PubMed Central PMCID: PMC3912766. )). ===== Side effects ===== PO or IV: somnolence and fatigue in 15%. Dizziness in 9%. Asthenia 15% and infection 13% (nasopharyngitis and influenza may or may not have been related). Keppra XR: somnolence 8%, irritability 6%.