Lack of pharmacokinetic interaction of levetiracetam on carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy

PURPOSE: To determine whether levetiracetam (LEV) affects plasma concentrations of carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy. METHODS: The potential for interaction of LEV with other antiepileptic drugs (AEDs) was assessed using plasma drug levels obtained in a randomized placebo-controlled phase III trial of adjunctive LEV in children receiving one or two concomitant AEDs. Multiple plasma AED levels at baseline and during adjunctive treatment with LEV or placebo were compared by repeated measures analysis of covariance and mean concentration ratios (treatment/baseline) were estimated with their 90% confidence intervals (CI). RESULTS: The study population included 187 children receiving any concomitant AED alone or in combination. The geometric mean concentrations at baseline and during LEV treatment were carbamazepine 8.4 microg/ml versus 8.1 microg/ml (coefficient of variation, CV = 30%; n = 35); valproic acid 83.8 versus 82.5 microg/ml (CV = 38%; n = 23); topiramate 7.3 versus 7.2 microg/ml (CV = 82%; n = 28); lamotrigine 8.2 versus 7.7 microg/ml (CV = 62%; n = 22). For each AED, the mean concentration ratios (LEV/baseline) and their 90% CIs showed that AED concentrations were unaffected by concomitant LEV administration. No differences were observed between LEV and placebo. CONCLUSIONS: LEV does not affect plasma concentrations of carbamazepine, valproic acid, topiramate, or lamotrigine in children with epilepsy.     

Adjunctive levetiracetam in infants and young children with refractory partial-onset seizures

Purpose:   To evaluate the efficacy and tolerability of adjunctive levetiracetam in very young children (aged 1 month to <4 years) with partial-onset seizures inadequately controlled with one or two antiepileptic drugs.
Methods:   This multicenter, double-blind, randomized, placebo-controlled study consisted of a 48-h inpatient baseline video-EEG (electroencephalography) and a 5-day inpatient treatment period (1-day up-titration; 48-h evaluation video-EEG in the last 2 days). Children who experienced at least two partial-onset seizures during the 48-h baseline video-EEG were randomized to either levetiracetam [40 mg/kg/day (age 1 to <6 months); 50 mg/kg/day (age ≥6 months to <4 years] or placebo.
Results:   Of 175 patients screened, 116 patients were randomized [60 levetiracetam; 56 placebo; intent-to-treat (ITT) population], and 111 completed the study. The responder rate in average daily partial-onset seizures frequency (48-h video-EEG monitoring; primary efficacy variable) was 43.1% for levetiracetam [modified ITT (mITT) = 58] versus 19.6% for placebo (mITT = 51; p=0.013), with odds ratio for response 3.11 [95% confidence interval (CI), 1.22–8.26]. The median percent reduction from baseline in average daily partial-onset seizure frequency was 43.6% for levetiracetam and 7.1% for placebo with a median difference between treatment groups of 39.2% (95% CI, 17.5–62.2; p   <   0.001). In general, levetiracetam was well tolerated. Treatment-emergent adverse events were reported by 55.0% levetiracetam- and 44.6% placebo-treated patients (ITT population). The most frequently reported adverse events were somnolence (13.3% levetiracetam, 1.8% placebo) and irritability (11.7% levetiracetam, 0% placebo).
Discussion:   Adjunctive levetiracetam is an efficacious and well-tolerated treatment for partial-onset seizures in infants and young children.     

Efficacy and tolerability of levetiracetam in children with epilepsy

Objective: To assess the efficacy and tolerability of levetiracetam (Lev) in children with epilepsy. Methods: Open-label observational, prospective, single arm, non-interventional study examining patients (?14 years) with epilepsy, receiving mono- or combination therapy with levetiracetam. Levetiracetam was started at a dose of approximately 10 mg/kg/day. The dose was titrated up with 10 mg/kg increments if seizures were poorly controlled but the maximum daily dose could not be more than 60 mg/kg/day. Documented were seizure type and frequency, levetiracetam dose and side effects. Results: 120 patients (39.3% females, mean age 4.5 ± 3.9 years) were enrolled. Average duration of follow-up was 10.3 ± 3.5 months. At study endpoint, 64.8% of patients got seizure free and 83.0% got a seizure reduction of ?50%. Observed side effects were somnolence, dysphoria, nervousness, dystrophy, somnipathy, asitia, debilitation, etc. and the incidence rate in the study was 47.5%. Four (3.3%) of 120 patients withdrew because of intolerance of side effects. The estimated one year retention rate of levetiracetam was 73.3%. Poor effect was the most common reason for withdrawal. Conclusions: In our study, it seemed that levetiracetam was safe and effective for a wide range of epileptic seizures in children with epilepsy.     

左乙拉西坦治疗小儿癫痫疗效的Meta分析

目的评价左乙拉西坦治疗小儿癫痫的疗效和安全性。方法计算机检索近十年(2001-2011)来PubMed、Cochrane Database of Systematic Reviews、EMbase、中国知网(CNKI)检索平台、万方数据库中纳入左乙拉西坦治疗小儿癫痫的随机对照研究(RCTs),研究者对文献质量进行严格评价和资料提取。对符合质量标准的RCTs用Review manager 5.0软件进行Meta分析。结果 6个RCTs共610名患者纳入研究,其中治疗组(使用左乙拉西坦)333例,对照组(常规治疗)277例。Meta分析结果表明治疗组患者每周癫痫发病率明显低于对照组,对于患者继发嗜睡、头痛等中枢系统不良反应及肝肾功能损害方面,RCTs结果显示无显著差异。结论左乙拉西坦治疗不良反应种类少,对各种发作类型的小儿癫痫均有良好疗效,且不增加发生其他不良结局的危险性,可作为小儿癫痫患者的首选治疗方案之一。     

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.     

Hair loss with levetiracetam in five patients with epilepsy

PurposeTo report cases of hair loss with levetiracetam (LEV) in epilepsy patient and summarise their demographic and clinical features.MethodAll patients reported attended the epilepsy outpatient clinic of the West China Hospital, Sichuan University. Demographic and clinical information was obtained from medical records and by interview. All the patients were under regular follow up.ResultsFive epilepsy patients (4 females and 1 male) are reported. All developed hair loss within two months of starting LEV treatment. Three had idiopathic epilepsy, two symptomatic epilepsy. Three patients received LEV monotherapy, two combination treatment. None decided to switch away from LEV to another drug after developing hair loss, although the dose of LEV was reduced in one patient.ConclusionHair loss may be a rare side effect of LEV treatment in patients with epilepsy. LEV-related hair loss appears reversible if the dose is reduced or treatment is stopped.     

Pharmacokinetic study of levetiracetam in children

PURPOSE: The pharmacokinetics of the novel antiepileptic drug (AED) levetiracetam and its major metabolite, ucb L057, were studied in children with partial seizures in a multicenter, open-label, single-dose study. METHODS: Twenty-four children (15 boys, nine girls), 6 to 12 years old, received a single dose of levetiracetam (20 mg/kg) as an adjunct to their stable regimen of a single concomitant AED, followed by a 24-h pharmacokinetic evaluation. RESULTS: In children, the half-lives of levetiracetam and its metabolite ucb L057 were 6.0 +/- 1.1 and 8.1 +/-2.7 hours, respectively. The Cmax and area under the curve (AUC) of levetiracetam equated for a 1-mg/kg dose were lower in children (Cmax, norm=1.33 plus minus 0.35 microg/ml; AUCnorm=12.4 +/- 3.5 microg/h/ml) than in adults (Cmax, norm=1.38 +/- 0.05 microg/ml; AUCnorm=11.48 +/- 0.63 microg/h/ml), whereas the renal clearance was higher. The apparent body clearance (1.43 +/- 0.36 ml/min/kg) was approximately 30-40% higher in children than in adults. Levetiracetam was generally well tolerated. CONCLUSIONS: On the basis of these data, a daily maintenance dose equivalent to 130-140% of the usual daily adult maintenance dosage (1,000-3,000 mg/day) in two divided doses, on a weight-normalized level (mg/kg/day) is initially recommended. Clinical efficacy trials in children are ongoing with dosages of 20 to 60 mg/kg/day.     

左乙拉西坦治疗60例小儿癫痫的疗效和安全性分析

目的探讨左乙拉西坦在小儿癫痫治疗中的疗效和安全性。方法从我院2013-06—2014-06小儿神经内科专科门诊部收治的癫痫患儿中随机性抽取60例作为研究对象,采用开放性自对照随访研究方法。60例患儿均给予左乙拉西坦口服治疗,随访6~10个月,观察治疗前后癫痫发作频率变化、脑电图改变情况以及患儿治疗期间的不良反应,评价左乙拉西坦治疗小儿癫痫的疗效和安全性。结果本组患儿均成功获得随访,治疗后完全控制26例,有效20例,无效12例,加重2例,总有效率76.67%,且不同类型癫痫患儿治疗后的发作次数明显低于治疗前(P0.01)。脑电图检查痫样放电消失31例,痫样放电减少50%以上10例,痫样放电减少25%~49%9例,痫样放电无变化7例,痫样放电增加3例。本组治疗期间18例发生不良反应,不良反应发生率30.00%,主要表现为情绪异常、嗜睡乏力、皮疹等症状,给予对症治疗后均得到缓解,无严重影响治疗的不良反应。结论左乙拉西坦治疗儿童癫痫的疗效确切,不良反应少,是一种安全有效的药物。     

左乙拉西坦联合盐酸舍曲林治疗癫痫伴抑郁患儿的疗效观察

目的 探讨左乙拉西坦联合盐酸舍曲林治疗癫痫伴抑郁症儿童的临床疗效。方法 回顾性分析112例6~15岁癫痫伴抑郁症的临床资料,按年龄分为学龄组（6~12岁,56例）和少年组（13~15岁,56例）,评估治疗前后癫痫发作频率、认知功能（WISC-CR）、汉密尔顿抑郁量表17项（HAMD-17）、生活质量、身体质量指数（BMI）、不良反应发生率。结果 与治疗前相比,两组治疗6、12个月,癫痫发作频率、认知功能、HAMD-17评分、生活质量均显著改善（P<0.05）;同时,学龄组癫痫发作频率、认知功能、HAMD-17评分、生活质量均显著优于少年组（P<0.05）;两组治疗后BMI、不良反应发生率无统计学差异（P>0.05）。结论 采用左乙拉西坦联合盐酸舍曲林治疗癫痫伴抑郁症儿童可获得显著的疗效,其中学龄组疗效优于少年组。     

Behavioral side-effects of levetiracetam in children with epilepsy: A systematic review

PurposeChildren with epilepsy are more likely to have behavioral problems compared to children without epilepsy. Literature suggests that levetiracetam leads to behavioral side-effects in children with epilepsy. The objective of this study is to provide a better overview of the frequency and variety of behavioral side-effects, which can be initiated by levetiracetam therapy in children with epilepsy.MethodElectronic databases used in the search were PubMed, Medline, Cochrane and Embase. Studies were eligible for inclusion when they included children from one month to 18 years of age with a diagnosis of epilepsy, used levetiracetam, had other AEDs on a stable regimen for at least two months, reported about behavioral side-effects and had a follow-up of at least two weeks. Quality assessments and data collection were carried out for all eligible studies.ResultsThirteen studies, including 727 patients using levetiracetam, were included in this systematic review. Three randomized controlled trials showed a total of 62 behavioral side-effects in 203 patients, effects which led to discontinuation of levetiracetam in only two of 102 patients (2.0%). Hostility, nervousness and aggression were reported mostly. Meta-analysis showed a statistically significant relative risk of 2.18 for the total number of behavioral side-effects for levetiracetam versus placebo. Observational studies showed mixed results with both behavioral deteriorations and improvements following levetiracetam.ConclusionBased on the findings in this systematic review, children using levetiracetam have a risk of developing several behavioral side-effects such as aggression, hostility and nervousness compared to children who do not use levetiracetam.     

No effect of oral contraceptives on the metabolism of levetiracetam

The effect on clearance of levetiracetam (LEV) was estimated in women with epilepsy of childbearing potential using oral contraceptives (OCs). The estimated clearance (plasma concentration/daily dose) was 39 nmol/L/mg (range 14-88 nmol/L/mg) among women who did not use OC (n=30) and 38 nmol/L/mg (range 18-103 nmol/L/mg) among OC users (n=23) (p=0.8). In conclusion, combing LEV and OCs seems safe from a pharmacokinetic perspective.     

Seizure-free days observed in randomized placebo-controlled add-on trials with levetiracetam in partial epilepsy

PURPOSE: We examined the effect of adjunctive levetiracetam (LEV; 1,000 to 3,000 mg/day) on the number of seizure-free days gained per quarter in adult patients with refractory partial-onset epilepsy. METHODS: The treatment effect was studied in a meta-analysis using individual patient data of a subpopulation of patients (n = 846) emerging from the three randomized, double-blind, placebo-controlled, phase III trials (n = 904). RESULTS: Adding LEV effectively increased the number of days without seizures by 5.19 days per quarter [95% confidence interval (CI), 3.63-6.76; p = 0.0001; titration and stable dose periods]. CONCLUSIONS: LEV adjunctive treatment shows a clear benefit in terms of seizure-free days gained for patients with refractory epilepsy. This gain is significant for the pooled and for each LEV dose compared with placebo.     

Efficacy and tolerability of levetiracetam in children younger than 4 years: a retrospective review

PURPOSE: To review our experience of the efficacy and tolerability of levetiracetam (LEV) in children younger than 4 years. METHODS: We used retrospective chart review to identify 122 children with seizures who were younger than 4 years and followed for >or=6 months. Efficacy was evaluated on the basis of the occurrence and durability of seizure remission. Tolerability was based on parent- and patient-reported side effects. RESULTS: Seventy (57%) subjects achieved seizure remission, and 52 (43%) did not. In univariate analysis, those achieving seizure remission were more likely to have partial epilepsy, require lower maintenance doses of LEV, and have fewer than two seizures per month at initiation of the medication. Only seizure frequency at initiation of LEV remained significant in multivariate analysis. The median duration of seizure freedom (8.9 month) was not influenced by age, epilepsy type, gender, or pretreatment seizure frequency. The dose of LEV was the only significant predictor of the duration of seizure remission, with longer duration of seizure remission seen in those taking <30 mg/kg/day compared with those taking > 30 mg/kg/day (median, 12.8 months vs. 3 months; p<0.0001). Side effects of LEV occurred in 34% of subjects but required discontinuation in only 16%, most commonly because of behavioral disturbances. CONCLUSIONS: LEV is an effective medication in children younger than 4 years and at doses lower than previously reported. It also well tolerated, suggesting that it represents an important option for the treatment of epilepsy in this age group.     

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.     

Randomized-controlled trials of levetiracetam as an adjunctive therapy in epilepsy of multiple seizure types

This meta-analysis aimed to systematically collect and synthesize the current evidence regarding the efficacy and tolerability of levetiracetam (LEV) as an adjunctive therapy for adults and children suffering from idiopathic and secondary epilepsy of multiple seizure types. We selected randomized-controlled trials (RCT) of LEV as an adjunctive therapy in epilepsy according to predefined criteria. Outcome measures included a ⩾50% reduction in seizure frequency, seizure freedom, and adverse events. Thirteen RCT were analyzed. Results showed that the efficacy of adjunctive LEV was superior to placebo both in achieving ⩾50% reduction in seizure frequency (pooled odds ratio [OR] 3.36, 95% confidence interval [CI] 2.78–4.07, Z = 12.46; p < 0.00001) and seizure freedom (pooled OR 4.72, 95% CI 2.96–7.54, Z = 6.50; p < 0.00001). The heterogeneity was mild (chi-squared = 12.28, I² = 2% in ⩾50% reduction in seizure frequency, and chi-squared = 0.49, I² = 0% in seizure freedom). Subgroup analysis suggested similar effects across different dosages in adults. The incidence of adverse reactions was not significantly different between the LEV group and the placebo group. The adverse events of relatively high incidence in the LEV group included somnolence, agitation, dizziness, asthenia, and infection. Incidence of serious adverse reaction such as rash and white blood cells and platelets decreasing was quite low. Adjunctive therapy with LEV was superior to placebo in reducing the frequency of seizures in patients with partial and idiopathic generalized epilepsy with effect in both adults and children, and demonstrated good tolerance in patients with epilepsy.     

Population pharmacokinetics of levetiracetam and dosing recommendation in children with epilepsy

Purpose:   To develop a population pharmacokinetic model to evaluate the demographic and physiologic determinants of levetiracetam (LEV) pharmacokinetics (PK) and to suggest recommended doses of LEV in children.
Methods:   LEV PK were investigated in a prospective open trial of LEV as adjunctive therapy using a population approach performed with NONMEM (Nonlinear Mixed Effects Model) on 170 LEV concentration–time records and covariate information from 44 children between 4 and 16 years of age. Possible associations between pharmacokinetic parameters and age, gender, body weight, creatinine clearance, and concomitant antiepileptic drugs (AEDs) were assessed. The final model was used to perform Monte Carlo simulations in order to identify the dosing regimens that should achieve the same nominal target concentration range as in adults.
Results:   LEV PK were well described by a one-compartment model with first-order absorption and elimination. Both LEV apparent clearance and distribution volume were related to body weight, and no pharmacokinetic interaction was observed. Monte Carlo simulations showed that a 10mg/kg twice daily (b.i.d.) regimen provides a plasma concentration similar to that obtained in adults for the recommended 500 mg b.i.d. starting dose, and that a 20 mg/kg b.i.d. regimen would achieve the previously described 6–20 mg/L target range for the trough concentration.
Discussion:   Our results support the use of a weight-based LEV dosing regimen and provide a basis for a recommended pediatric dosage regimen. The relationship between LEV plasma concentrations and clinical effect has not been evaluated fully and could differ between adults and children. Clinical studies should be able to validate these dosing recommendations.     

Dramatic weight loss with levetiracetam

BACKGROUND: Levetiracetam is considered a "weight-neutral" drug. We report 19 cases of significant weight loss associated with levetiracetam at a dose ranging from 500 to 2000 mg/day. METHODS: The population was divided into two groups. Group 1 includes patients in whom levetiracetam was the only possible cause of weight loss and Group 2 those in whom other factors may have played a role. Similar cases reported by the French national drug safety center were added (Group 3). RESULTS: Group 1 included 9 females and 3 males (weight loss ranging from 8.1% to 28.6%). Three patients had levetiracetam in monotherapy. Prior levetiracetam only three were overweight. One patient was hospitalized for a thorough assessment of weight loss. Seven patients reported reduced caloric intake due to decreased pleasure with food. The other five did not report any changes in feeding behavior. Group 2 included seven females with a weight loss ranging from 10% to 26.6%. One patient was on topiramate since two years prior to levetiracetam. Weight loss started with the introduction of levetiracetam. In 4 patients, there was a decreased dosage or cessation of a previous drug known to produce weight gain in some cases simultaneously to the introduction of levetiracetam, but in two of these patients these drugs had not produced any weight gain. Group 3 included only two patients (weight loss: 7 and 20 kg). CONCLUSIONS: This study provides evidence that levetiracetam can cause significant weight loss. Women are at higher risk while initial weight is not a factor.     

左乙拉西坦添加治疗成人癫痫的疗效

目的：研究左乙拉西坦（LEV）添加治疗成人癫痫的临床疗效及安全性。方法选取江苏大学附属人民医院2010年1月～2013年12月收治的成人癫痫患者116例为研究对象。采取多阶段分层抽样法将患者分为LEV添加治疗组和常规治疗组,同时行开放性自身对照研究,观察并比较两组患者的癫痫发作控制率、治疗有效率和不良反应。结果 LEV添加治疗组的总有效率为77．6％;常规治疗组为51．7％,两组疗效的差异存在统计学意义（P＜0．01）。LEV添加治疗组不良反应（包括嗜睡、头晕、食欲下降和兴奋激动）发生率为19．0％;常规治疗组不良反应发生率为17．2％,两组的差异无统计学意义（P ＞0．05）。结论 LEV添加治疗与常规治疗相比,对各种发作类型的成人癫痫均有较好疗效,且安全性较好。