Levetiracetam,a new antiepileptic agent: lack of in vitro and in vivo pharmacokinetic interaction with valproic acid

PURPOSE: The novel antiepileptic drug (AED) levetiracetam (LEV; Keppra) has a wide therapeutic index and pharmacokinetic characteristics predicting limited drug-interaction potential. It is indicated as an add-on treatment in patients with epilepsy, and thus coadministration with valproic acid (VPA) is likely. These studies were performed to determine whether coadministration of LEV with VPA might result in pharmacokinetic interactions. METHODS: In vitro assays were performed to characterize the transformation of LEV into its main in vivo metabolite UCB L057. The reaction was examined for its sensitivity to clinically relevant concentrations of VPA. An open-label, one-way, one-sequence crossover clinical trial was conducted in 16 healthy volunteers to assess further the possibility of any relevant pharmacokinetic interaction. RESULTS: Human whole blood and, to a lesser extent, human liver homogenates were demonstrated to hydrolyze LEV to UCB L057, its main metabolite. The reaction possibly involves type-B esterases and is not affected by 1 mM VPA (i.e., 166 microg/ml). Pharmacokinetic parameters of a single dose of LEV (1,500 mg) coadministered with steady-state concentrations of VPA (8 days of 500 mg, b.i.d.) did not differ significantly from the pharmacokinetics of LEV administered alone [area under the curve (AUC) of 397 and 400 microg/h/ml, respectively]. Furthermore, LEV did not affect the steady-state pharmacokinetics of VPA. CONCLUSIONS: These findings suggest the absence of a pharmacokinetic interaction between VPA and LEV during short-term administration, and suggest that dose adjustment is not required when these two drugs are given together.     

Levetiracetam does not alter the pharmacokinetics of an oral contraceptive in healthy women

PURPOSE: This study was designed to evaluate whether levetiracetam, a novel antiepileptic drug (AED), influences the pharmacokinetics of steroid oral contraceptives. METHODS: During a run-in phase, 18 healthy female patients received an oral contraceptive containing ethinyl estradiol, 0.03 mg, and levonorgestrel, 0.15 mg, for the first 21 days of two consecutive menstrual cycles. In a subsequent double-blind, randomized, two-way crossover treatment phase, subjects received either levetiracetam, 500 mg, or placebo twice daily concomitant with the oral contraceptive. Plasma concentrations of ethinyl estradiol and levonorgestrel were measured on days 14 and 15 of the two treatment periods for the evaluation of the 24-h kinetic parameters, and an additional sample was collected on day 21 to determine the trough plasma concentrations. Serum progesterone and luteinizing hormone (LH) levels were determined on days 13, 14, 15, and 21 of each cycle of the treatment phase. RESULTS: The plasma concentration-time curves and pharmacokinetic parameters of ethinyl estradiol and levonorgestrel were not statistically different during concomitant treatment with either levetiracetam or placebo. The ratios of the log-transformed geometric mean areas under the plasma concentration-time curves (AUCs), maximal (Cmax) and minimal (Cmin) plasma concentrations, and trough concentrations on day 21 (C21) ranged from 99.12 to 99.96% for ethinyl estradiol and from 97.13 to 99.41% for levonorgestrel. The 90% confidence intervals of these ratios were well within the 80 to 125% acceptance range for lack of interaction. Serum progesterone and LH concentrations were fairly constant during the run-in and treatment phases and remained markedly below their respective physiologic levels. Safety and menstrual-bleeding patterns were comparable during levetiracetam and placebo administration. CONCLUSIONS: Levetiracetam does not affect the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and levonorgestrel, and on the basis of serum progesterone and LH levels, it does not affect the contraceptive efficacy.     

Levetiracetam psychosis in children with epilepsy

PURPOSE: Levetiracetam is a new anticonvulsant (AED) with a novel mechanism of action. Although it is generally well tolerated with a good cognitive profile, irritability and hostility have been reported in some adults taking levetiracetam. Observations in children are limited; levetiracetam is not yet approved by the Food and Drug Administration for use in children. METHODS: In four young patients, acute psychosis developed within days to months of initiation of levetiracetam for seizures. RESULTS: A 5-year-old girl began having visual hallucinations of spiders in her room 14 days after starting levetiracetam. A 13-year-old boy began having auditory hallucinations, insomnia, and screaming behavior 3 months after initiation of levetiracetam. A 16-year-old girl became acutely agitated, hyperreligious, and had persecutory delusions within 7 days of starting levetiracetam. A 17-year-old girl had auditory hallucinations telling her to sing and yell after 30 days of taking the drug. All four children had dramatic improvement within days of either discontinuing or decreasing the dose of levetiracetam. The three adolescents had historical findings consistent with mild behavioral problems before initiating levetiracetam, and all four patients had prior cognitive deficits. CONCLUSIONS: Reversible treatment-emergent psychosis associated with levetiracetam therapy was observed in four children and adolescents. Whether rapid initiation or prior neurobehavioral problems predispose to this side effect is not established.     

Levetiracetam in focal epilepsy and hepatic porphyria: a case report

We report a patient with focal epilepsy and latent hereditary coproporphyria who had exacerbation of clinical symptoms of porphyria under treatment with valproate and primidone and was then treated with levetiracetam without exacerbation of clinically latent porphyria.     

左乙拉西坦治疗癫痫的疗效及安全性的随访分析

目的观察左乙拉西坦(LEV商品名Keppra)单药或添加治疗儿童及成人各类型癫痫的临床疗效及安全性。方法采用开放性自身对照的研究方法,以四川大学华西医院神经内科自2008年2月～2009年6月收治的80例门诊和住院癫痫患者为研究对象,对其进行6个月的LEV治疗并随访,观察LEV对癫痫患者的疗效及不良反应。结果80例随访观察对象接受LEV治疗≥6个月后,达到完全控制的为15例,占18.8%;LEV治疗有效的35例,占43.7%;而有30例患者对LEV治疗无效,占37.5%,即总应答率为62.5%。总体上LEV添加或单药治疗各种类型癫痫临床效果肯定,患者年龄、病程、是否有头部影像学异常对其疗效影响不大,单药治疗或添加治疗癫痫的临床疗效亦无统计学差异,而与癫痫的类型相关,LEV对复杂部分性发作继发全面性发作疗效最好(应答率79.5%)。随访过程中失访6例(7.8%),出现不良反应9例(11.3%)。结论LEV作为一种新型抗癫痫药物,单药治疗或添加治疗成人及儿童各种类型癫痫具有较好的疗效和安全性。     

Levetiracetam efficacy in epileptic syndromes with continuous spikes and waves during slow sleep: experience in 12 cases

PURPOSE: To assess the add-on efficacy of levetiracetam on the EEG, behavior, and cognition of children with continuous spikes and waves during slow sleep (CSWS). METHODS: Charts of children with behavioral and/or cognitive deterioration associated with CSWS who received levetiracetam at 50 mg/kg/day as add-on treatment were retrospectively reviewed. Awake and sleep EEG recordings and detailed neuropsychological and behavioral assessments were available at baseline and 2 months after levetiracetam initiation. In children showing clinical and/or electrophysiological improvement after 2 months, levetiracetam was continued with a new evaluation at 1 year. RESULTS: Twelve patients were included (9 cryptogenic and 3 symptomatic cases). Seven patients (58.3%) showed improvement of EEG record. Among these seven patients, neuropsychological evaluation was improved in three, and in the other four patients, not testable because of severe cognitive impairment, behavior was improved. Two patients improved in neuropsychological evaluation despite the lack of EEG improvement. Eight patients (66.6%) continued levetiracetam treatment after 2 months. After 1 year, four patients were still on levetiracetam, two because sustained effect on EEG and behavior and the two others because improvement in neuropsychological testing despite unchanged EEG. Levetiracetam was discontinued in the other four patients because of neuropsychological or behavioral deterioration associated with CSWS pattern, between 9 and 11 months after treatment initiation. CONCLUSIONS: This retrospective study suggests that levetiracetam has a positive effect on the EEG, the behavior, and the cognition of patients with epilepsy and CSWS. Additional studies are warranted in order to assess the place of this drug in these epileptic conditions.     

Pharmacokinetics of levetiracetam during pregnancy, delivery, in the neonatal period, and lactation

PURPOSE: To study pharmacokinetics of levetiracetam (LEV) during pregnancy, delivery, lactation, and in the neonatal period. METHODS: Fourteen women with epilepsy receiving LEV treatment during pregnancy and lactation contributed with 15 pregnancies to this prospective study in which LEV concentrations in plasma and breast milk were determined. Trough maternal plasma samples were collected each trimester, and at baseline after delivery. Blood samples were obtained at delivery from mothers, from the umbilical cord, and from newborns during 2 days after delivery. LEV concentration was also determined in breast milk and in plasma collected from 11 of the mothers and their suckling infants after birth. RESULTS: The umbilical cord/maternal plasma concentration ratios ranged from 0.56-2.0 (mean 1.15, n=13). LEV plasma concentrations in the neonates declined with an estimated half-life of 18 h (n=13). The mean milk/maternal plasma concentration ratio was 1.05 (range, 0.78-1.55, n=11). The infant dose of LEV was estimated to 2.4 mg/kg/day, equivalent to 7.9% of the weight-normalized maternal dose. Plasma concentrations in breastfed were approximately 13% of the mother's plasma levels. Maternal plasma concentrations during third trimester were only 40% of baseline concentrations outside pregnancy (p<0.001, n=7) CONCLUSIONS: Our observations suggest considerable transplacental transport of LEV and fairly slow elimination in the neonate. Plasma concentrations of LEV in nursed infants are low despite an extensive transfer of LEV into breast milk. Pregnancy appears to enhance the elimination of LEV resulting in marked decline in plasma concentration, which suggests that therapeutic monitoring may be of value.     

Levetiracetam intravenous infusion: a randomized, placebo-controlled safety and pharmacokinetic study

PURPOSE: The primary objective of this placebo-controlled study was to evaluate the safety and tolerability of levetiracetam (LEV) administered intravenously (IV) at higher doses and/or at a faster infusion rate than proposed. The secondary objective was to assess LEV pharmacokinetics. METHODS: Single ascending doses of LEV administered by IV infusion (2,000, 3,000, 4,000 mg over 15 min; 1,500, 2,000, 2,500 mg over 5 min) were evaluated in 48 healthy subjects in a randomized, single-blind, placebo-controlled study. RESULTS: All randomized subjects completed the study. Adverse events reported after IV administration of LEV (相似文献   

Levetiracetam for people with mental retardation and refractory epilepsy

Levetiracetam (LEV) is a novel antiepileptic drug (AED) with efficacy against a wide range of seizures types. The aim of this observational study was to assess its effectiveness in patients with mental retardation and refractory epilepsy. Sixty-four patients were started on adjunctive LEV after a 3-month baseline. LEV was initially dosed at 250 mg daily and increased by 250 mg every 2 weeks thereafter according to clinical response. Caregivers rated the patient's sleep, appetite, alertness, and behavior as poor (1), reasonable (2), or good (3) at each clinic visit. Patients were reviewed until one of four endpoints was reached: seizure freedom for at least 6 months, > or = 50% reduction in seizure frequency (responder) over a 6-month period, <50% reduction in seizure frequency (marginal effect) over a 6-month period, or LEV withdrawal due to lack of efficacy, adverse effects, or both. Twenty-four (38%) patients became seizure-free, 10 of whom were controlled on LEV 250 mg twice daily. An additional 18 (28%) patients were classified as responders, and 8 (12%) reported only marginal benefit from adjunctive LEV. Fourteen (22%) patients discontinued LEV (6 worsening seizures, 1 lack of efficacy, 7 adverse effects). Caregivers rated combined sleep, appetite, alertness, and behavior scores as "improved" at the end of follow-up (P<0.001). LEV improved seizure control in the majority of patients with mental retardation and may also have enhanced their quality of life.     

Levetiracetam efficacy in refractory partial-onset seizures,especially after failed epilepsy surgery

PURPOSE: We conducted a retrospective study to evaluate the efficacy of levetiracetam as adjunctive therapy in patients with localization-related epilepsy, and specifically in the subset of patients for whom epilepsy surgery failed. METHODS: Eighty-two patients with uncontrolled partial-onset seizures treated with levetiracetam were identified; epilepsy surgery had failed for 21 (25.6%; group I), and 61 (74.4%) had no prior surgery (group II). Group I and group II patients were comparable in age (mean, 40.7 vs. 41.5 years) and age at seizure onset (mean, 14.4 vs. 18.2 years). Patients who had >/=50% reduction in seizure frequency were considered responders; the remaining patients were considered nonresponders. RESULTS: In patients (group I) for whom surgery had failed, responder rate was 76.1% (16 of 21), including 10 (47.6%) patients who became seizure free. In nonsurgical patients (group II), responder rate was 34.3% (21 of 61), including nine (14.7%) patients who became seizure free. In group I, 11 (91.6%) of 12 temporal resection patients were responders, of whom eight were seizure free; of the remaining nine operated (extratemporal) patients, five (55.5%) were responders, and two were seizure free. In three responders, all in group I, a severe, delayed psychotic syndrome developed 4 to 9 months after levetiracetam introduction, leading to its discontinuation. CONCLUSIONS: These findings suggest that adjunctive levetiracetam therapy should be considered early after failed epilepsy surgery, especially after temporal resection, and may have implications for its use before surgical intervention. Patients should be under close psychiatric observation in this clinical setting.     

左乙拉西坦治疗癫（癎）伴认知功能障碍患儿疗效观察

目的 分析左乙拉西坦治疗癫（癎）伴认知功能障碍患儿的临床疗效.方法 选择在本院接受治疗的癫（癎）伴认知功能障碍患儿作为研究对象,分别给予常规治疗及左乙拉西坦治疗,比较2组患儿的认知功能、脑电活动情况及生活质量评分等差异.结果 观察组总有效率（66.67%）、MMES评分（25.47±4.83）、无认知功能障碍（83.33%）、躯体功能（76.87±7.16）、心理功能（59.32±5.34）、社会功能（58.76±2.16）、总体生活质量（82.34±8.21）评分均明显高于对照组（P〈0.05）;癫（癎）样放电（15%）、α波（18.21±3.36）、β波（10.32±2.25）、δ（12.36±2.25）、θ波（20.32±3.24）数目均明显少于对照组（P＜0.05）.结论 左乙拉西坦可有效改善癫（癎）伴认知功能障碍患儿的认知功能,减少异常脑电活动,提高生活质量.     

Levetiracetam in children with refractory epilepsy: Lack of correlation between plasma concentration and efficacy

PurposeThe goals of this study are to evaluate the efficacy and tolerability of levetiracetam (LEV) as add-on therapy in children with refractory epilepsies and to determine the value of LEV blood level monitoring in this population.MethodsSixty-nine children (39 males and 30 females) treated with LEV between 2006 and 2007 were selected. Their medical files were reviewed for LEV efficacy and tolerability. In a subgroup of children currently taking LEV, plasma concentrations were determined by high performance liquid chromatography by ultraviolet detection (HPLC-UV) method and correlated with the given dose per kilo as well as clinical response.ResultsFifty-one patients (74%) had a more than 50% reduction in seizure frequency with 16 patients (23%) becoming seizure free on LEV. Eighteen (26%) patients had a less than 50% reduction in seizure frequency. Adverse events due to LEV ranged from mild to moderate in only 18 patients (26%). The most frequently observed were drowsiness, behavioral difficulties, increase in seizure frequency and headaches. The majority (60.5%) of the responders received doses between 10 and 50 mg/kg/day and had a plasma concentration (PC) between 5 and 40 μg/ml. However, we found no clear correlation between PC and efficacy.ConclusionLevetiracetam given twice a day in children with refractory epilepsy reduces seizure frequency in all types of epilepsy. In children, LEV is a broad spectrum anticonvulsant with a favourable safety profile.     

Levetiracetam pharmacokinetics in neonates at birth

Based on blood sampling in a formula-fed pair of twins, the estimated serum half-life of levetiracetam (LEV) at birth is 16-18 h.     

Measurement of levetiracetam drug levels to assist with seizure control and monitoring of drug interactions with other anti-epileptic medications (AEMs)

PurposeLevetiracetam (LEV) therapeutic range (20–40 mg/L) and potential drug interactions were assessed in people with epilepsy (PWE).MethodFifty-two PWE had LEV and concomitant medications [carbamazepine (CBZ); valproate (VPA); lamotrigine (LTG)] blood levels measured and compared to seizure activity. Lacosamide (LCM) levels were unavailable. Adopted therapeutic ranges were: 20–40 mg/L – LEV; 25–50 μmol/L – total CBZ; 6–13 μmol/L – free CBZ; 300–750 μmol/L – total VPA; 30–75 μmol/L – free VPA; and 40–60 μmol/L – LTG. Seizure-freedom was assessed and patients followed for almost two years.Results23 of 52 PWE (44%) used LEV monotherapy and 16/23 (70%) had ‘therapeutic’ LEV with 13/16 (81%) seizure-free. 29 of 52 (56%) used polytherapy and 16/29 (55%) had ‘therapeutic’ LEV with 7/16 (44%) seizure-free. 11 of 29 (38%) used CBZ: 4/11 (36%) had therapeutic mean LEV levels and 7/11 (64%) were seizure-free. Fourteen (48%) used VPA: 9/14 (64%) had therapeutic mean LEV levels and 8/14 (57%) were seizure-free. 13 of 29 (45%) used LTG: 8/13 (62%) had therapeutic mean LEV levels and 5/13 (38%) were seizure-free. LEV did not alter CBZ, but CBZ affected LEV. LEV elevated VPA free levels but not VPA total levels. Dosage/concentration was lowered with polytherapy.ConclusionLEV range (20–40 mg/L) assisted epilepsy management and anti-epileptic medication interactions were suggested with polytherapy thus possibly explaining the impaired efficacy of LEV with polytherapy.     

Economic Evaluation of Add-on Levetiracetam for the Treatment of Refractory Partial Epilepsy in Korea

Objective

This study estimated the expected cost-effectiveness ratio expressed as the incremental cost per seizure-free day (SFD) gained and the incremental cost per quality adjusted life year (QALY) gained when using levetiracetam (LEV) as add-on therapy from a third-party payer perspective.

Methods

A 1-year dose-escalation decision-tree model comparing LEV plus standard therapy (ST) with ST alone was designed to combine transition probabilities, costs and outcomes. The short-term outcomes and probabilities were derived from a prospective, open-label clinical trial with 100 Korean adults with refractory partial epilepsy. All data for the direct medical costs were derived from Korean cost data extracted from reports published by the National Health Insurance Corporation.

Results

The average gain in SFDs attributed to LEV add-on was 18.3 days per patient per year and the incremental cost-effectiveness ratios (ICERs) for LEV add-on were US$ 44 per SFD per patient and US$ 11,084 per QALY gained. All sensitivity analyses showed that the model was robust to the assumptions made.

Conclusion

The economic evaluation indicates that, given a wide range of assumptions, the increased cost of treating patients having refractory partial epilepsy with LEV may be partially offset by a reduction in other direct medical costs. This reduction is a consequence of an increase in the number of SFDs and improved quality of life.     

Levetiracetam extended release and levetiracetam immediate release as adjunctive treatment for partial-onset seizures: An indirect comparison of treatment-emergent adverse events using meta-analytic techniques

The safety profiles of once-daily adjunctive levetiracetam (LEV) extended release (XR) (1000 mg/day) and adjunctive LEV immediate release (IR) (500 mg twice daily) were compared using data from three randomized, placebo (PBO)-controlled phase III clinical trials in patients with partial-onset seizures. MedDRA 9.0 treatment-emergent adverse events (TEAEs) were indirectly compared using meta-analytic techniques, including calculation of risk difference (RD) and mixed-effects analysis. Statistical significance was set at 10% alpha risk, the normative value for these analyses. Data from 555 patients older than 16 (204 LEV IR, 70 LEV XR, 281 PBO) were analyzed. Following adjustment for incidence of placebo TEAEs, LEV XR showed statistically significantly lower rates of TEAEs than LEV IR across nervous system disorders (RD = −18%, P = 0.03), psychiatric disorders (RD = −11%, P = 0.08), and metabolism and nutrition disorders (RD = −3%, P = 0.08). Among nervous system disorders, the RD for headache favored LEV XR (RD = −11%, P = 0.08). These results suggest that adjunctive LEV XR may be associated with a lower incidence of nervous system, psychiatric, and nutritional and metabolic TEAEs as compared with LEV IR. However, this difference was observed at a broad scale and not at a specific TEAE level except for headache.     

左乙拉西坦和托吡酯对癫(疒间)大鼠脑P-糖蛋白表达的影响

目的研究左乙拉西坦(LEV)和托吡酯(TPM)对癫大鼠脑P-糖蛋白(P-gp)表达的影响。方法将海人酸1.5μg(3μl)注射至SD大鼠海马制作癫模型(癫组),对照组大鼠海马注射3μl生理盐水(NS)。将癫组(18只)和对照组(15只)大鼠分别随机分为LEV、TPM和NS亚组(每亚组6只、5只),各亚组大鼠予相应药物(LEV50mg/kg、TPM40mg/kg、等体积NS)灌胃,每天1次,共30d。采用免疫组化EnVi-sion染色法检测大鼠颞叶、海马P-gp表达水平,采用LeicaQwin图像分析系统中平均整合灰度(MIB)值对P-gp表达水平进行半定量分析。结果癫各亚组大鼠颞叶和海马P-gp表达水平(MIB值)均显著高于其相应对照亚组(P<0.05～0.001);对照亚组中,LEV和TPM组与NS亚组间P-gp表达水平比较,差异无统计学意义;在癫组中,TPM亚组P-gp表达水平显著高于NS亚组(1550.3±371.9vs1049.7±282.8,P=0.004);而LEV亚组与NS亚组差异无统计学意义(1285.1±340.3vs1049.7±282.8,P=0.172)。结论癫发作可诱导...     

左乙拉西坦和传统抗癫痫药体外诱导大鼠星形胶质细胞P糖蛋白表达的研究

目的研究左乙拉西坦(LEV)和传统抗癫痫药(AEDs)丙戊酸钠(VPA)、卡马西平(CBZ)对大鼠皮质星形胶质细胞P-糖蛋白(P-gp)的表达的影响。方法不同浓度(1、10、50、100μg·m L-1)的VPA、CBZ及LEV持续作用于培养的正常新生鼠大脑皮质星型胶质细胞,分别在给药后10、20和30d,用免疫细胞化学法检测P-gp的表达率。结果对照组即无药物作用的正常星形胶质细胞P-gp表达率在各时点均小于5%;CBZ组100μg·m L-1在20d,30d较对照组表达增高(P0.05),20d与30d两组间比较,P0.05,其他浓度与对照组比较P0.05;VPA组100μg·m L-1在30d时较对照组表达增高(P0.05),较20d时表达增高(P0.05),其他浓度较各时点对照组比较,P0.05。LEV组在各浓度,不同时点与对照组比较差异无统计学意义(P0.05)。结论高浓度CBZ、VPA可诱导星形胶质细胞P-gp的表达,而LEV不能诱导星形胶质细胞P-gp表达。     

Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group

PURPOSE: To evaluate the efficacy and tolerability of levetiracetam (LEV) monotherapy in selected patients with refractory partial seizures. METHODS: In this multicenter, double-blind, placebo-controlled, parallel-group, responder-selected study, patients were randomized (2:1 ratio) to receive oral LEV 1500 mg twice daily or placebo during a 12-week add-on phase. Treatment responders (patients with a reduction in partial seizure frequency of 50% or more compared with baseline) entered a monotherapy phase that included a maximum 12-week down-titration period and 12 weeks of monotherapy at 1500 mg twice daily. In both phases, responder rate, seizure frequency, and adverse events were analyzed. RESULTS: A total of 286 patients (placebo, n = 105; LEV, n = 181) entered the add-on phase, and 86 patients (placebo, n = 17; LEV, n = 69) were eligible for the monotherapy phase. Thirty-six of 181 patients (19.9%) who received LEV completed the entire study compared with only 10 of 105 patients (9.5%) in the placebo group (p = 0.029). The odds of completing the study on LEV were 2.36 times (95% confidence interval, 1.08, 5.57) higher than on placebo. The responder rate during the add-on phase was significantly higher in the LEV group compared with the placebo group (42.1% vs. 16.7%, respectively; p < 0.001). In the LEV monotherapy group, the median percent reduction in partial seizure frequency compared with baseline was 73.8% (p = 0.037), with a responder rate of 59.2%. Nine patients (18.4%) remained seizure-free on LEV monotherapy. CONCLUSIONS: Conversion to LEV monotherapy (1500 mg twice daily) is effective and well tolerated in patients with refractory partial seizures who responded to 3000 mg/d LEV as add-on therapy.