Posts Tagged Antiepileptic drug

[Abstract + References] Epilepsy and Anticonvulsant Therapy in Brain Tumor Patients – Book Chapter

Book Chapter

Authors: Sylvia C. Kurz, David Schiff, Patrick Y. Wen

Abstract

Seizures are common in patients with brain tumors and may have a significant impact on quality of life. The actual seizure risk varies based on tumor histology and tumor location. Seizures are most common in patients with glioneuronal tumors and temporal, insular, or frontal lobe tumor location. Antiepileptic drug therapy is indicated in patients with a history of seizure, and the choice of symptomatic treatment should follow the principles of treatment for focal symptomatic epilepsy. In general, antiepileptic drugs that interact with the hepatic CYP450 co-enzymes should be avoided in brain tumor patients if possible due to potential drug-chemotherapy interactions. Levetiracetam represents the antiepileptic drug of choice in patients with brain tumors and has been demonstrated to be efficacious and is well tolerated in brain tumor patients. Lacosamide is an alternative anticonvulsant agent with increasing experience supporting its efficacy and favorable side effect profile.

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[Abstract + References] How safe is switching antiepileptic drug manufacturers?

A nationwide German study of prescription data has demonstrated that switching to an antiepileptic drug from a different manufacturer increases the risk of seizure relapse. This finding sparks a debate about the reason for seizure worsening after switching and whether or not it is a pharmacological issue.

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    Ting, T. J. et al. Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: a field test of the FDA bioequivalence standard. Epilepsia 56, 1415–1424 (2015).

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    Privitera, M. D. et al. Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial. Lancet Neurol. 15, 365–372 (2016).

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    Gollwitzer, S. et al. Nonadherence to antiepileptic drugs in Germany: a retrospective, population-based study. Neurology 87, 466–472 (2016).

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    Kesselheim, A. S. et al. Variations in pill appearance of antiepileptic drugs and the risk of nonadherence. JAMA Intern. Med. 173, 202–208 (2013).

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    Holtkamp, M. & Theodore, W. H. Generic antiepileptic drugs — safe or harmful in patients with epilepsy? Epilepsia 59, 1273–1281 (2018).

via How safe is switching antiepileptic drug manufacturers? | Nature Reviews Neurology

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[Abstract] Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy

Abstract

Objective To characterize the magnitude and time course of pregnancy-related clearance changes for different antiepileptic drugs (AEDs): levetiracetam, oxcarbazepine, topiramate, phenytoin, and valproate. A secondary aim was to determine if a decreased AED serum concentration was associated with increased seizure frequency.

 

Methods Women with epilepsy were enrolled preconception or early in pregnancy and prospectively followed throughout pregnancy and the first postpartum year with daily diaries of AED doses, adherence, and seizures. Study visits with AED concentration measurements occurred every 1–3 months. AED clearances in each trimester were compared to nonpregnant baseline using a mixed linear regression model, with adjustments for age, race, and hours postdose. In women on monotherapy, 2-sample t test was used to compare the ratio to target concentrations (RTC) between women with seizure worsening each trimester and those without.

 

Results AED clearances were calculated for levetiracetam (n = 18 pregnancies), oxcarbazepine (n = 4), topiramate (n = 10), valproate (n = 5), and phenytoin (n = 7). Mean maximal clearances were reached for (1) levetiracetam in first trimester (1.71-fold baseline clearance) (p = 0.0001), (2) oxcarbazepine in second trimester (1.63-fold) (p = 0.0001), and (3) topiramate in second trimester (1.39-fold) (p = 0.025). In 15 women on AED monotherapy, increased seizure frequency in the first, second, and all trimesters was associated with a lower RTC (p < 0.05).

 

Conclusion AED clearance significantly changes by the first trimester for levetiracetam and by the second trimester for oxcarbazepine and topiramate. Lower RTC was associated with seizure worsening. Early therapeutic drug monitoring and dose adjustment may be helpful to avoid increased seizure frequency.

 

via Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy | Neurology

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[ARTICLE] Brivaracetam: a novel antiepileptic drug for focal-onset seizures . – Full Text

Brivaracetam (BRV), the n-propyl analogue of levetiracetam (LEV), is the latest antiepileptic drug (AED) to be licensed in Europe and the USA for the adjunctive treatment of focal-onset seizures with or without secondary generalization in patients aged 16 years or older. Like LEV, BRV binds to synaptic vesicle protein 2A (SV2A), but BRV has more selective binding and a 15- to 30-fold higher binding affinity than LEV. BRV is more effective than LEV in slowing synaptic vesicle mobilization and the two AEDs may act at different binding sites or interact with different conformational states of the SV2A protein. In animal models, BRV provides protection against focal and secondary generalized seizures and has significant anticonvulsant effects in genetic models of epilepsy. The drug undergoes first-order pharmacokinetics with an elimination half-life of 7–8 h. Although BRV is metabolized extensively, the main circulating compound is unchanged BRV. Around 95% of metabolites undergo renal elimination. No dose reduction is required in renal impairment, but it is recommended that the daily dose is reduced by one-third in hepatic dysfunction that may prolong half-life. BRV has a low potential for drug interactions. The efficacy and tolerability of adjunctive BRV in adults with focal-onset seizures have been explored in six randomized, placebo-controlled studies. These showed significant efficacy outcomes for doses of 50–200 mg/day. The most common adverse events reported were headache, somnolence, dizziness, fatigue and nausea. Patients who develop psychiatric symptoms with LEV appear to be at risk of similar side effects with BRV, although preliminary data suggest that these issues are likely to be less frequent and perhaps less severe. As with all AEDs, a low starting dose and slow titration schedule help to minimize side effects and optimize seizure control and thereby quality of life.

Epilepsy is the most common chronic neurological condition. Globally, 65 million individuals are affected1 and the diagnosis is made in an estimated 2.4 million people each year.2 Despite the availability of over 14 new antiepileptic drugs (AEDs) during the past three decades, repeated outcome analyses show that >30% fail to achieve prolonged seizure freedom with medical treatment.35 The introduction of novel agents is, therefore, welcome. Brivaracetam (BRV) is the latest AED to be licensed in Europe and the USA for the adjunctive treatment of focal-onset seizures with or without secondary generalization in patients aged 16 years or older. This article discusses the pharmacological properties of BRV, its performance in regulatory studies, details of its efficacy, tolerability and safety profiles and its place in everyday clinical practice.

BRV was discovered during a large-scale programme aimed at optimizing pharmacodynamic activity at a novel molecular AED target.6 It is the n-propyl analogue of levetiracetam (LEV; Figure 1), which acts as a high-affinity ligand for synaptic vesicle protein 2A (SV2A). SV2A is an integral transmembrane glycoprotein expressed in neurons and endocrine cells, which is involved in the modulation of synaptic vesicle exocytosis and neurotransmitter release.7 It also appears to have an important role in epileptogenesis, since SV2A deficiency in transgenic mice leads to increased seizure vulnerability.6

figure

Figure 1. Chemical structures of levetiracetam and brivaracetam.

[…]

Continue —> Brivaracetam: a novel antiepileptic drug for focal-onset seizuresTherapeutic Advances in Neurological Disorders – Linda J. Stephen, Martin J. Brodie, 2017

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[Abstract] Can High-Dose Levetiracetam Be Safe? A Case Report of Prolonged Accidental High-Dose Levetiracetam Administration and Review of the Literature

Levetiracetam is an antiepileptic drug that has been used both as adjunctive therapy and monotherapy in pediatric patients with epilepsy. We report a patient with cerebral palsy and epilepsy who took 200 mg/kg per day of levetiracetam for 55 days with no apparent adverse effects. Four other cases of accidental overdose were found in the literature; none of these was associated with any apparent adverse effects. These findings suggest that, in at least some cases, levetiracetam doses much higher than the recommended maximum of 60 mg/kg per day can be administered without apparent adverse effects.

Source: Can High-Dose Levetiracetam Be Safe? A Case Report of Prolon… : Clinical Neuropharmacology

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[ARTICLE] Rates and Predictors of Seizure Freedom With Vagus Nerve Stimulation for Intractable Epilepsy – Full Text

Abstract

BACKGROUND: Neuromodulation-based treatments have become increasingly important in epilepsy treatment. Most patients with epilepsy treated with neuromodulation do not achieve complete seizure freedom, and, therefore, previous studies of vagus nerve stimulation (VNS) therapy have focused instead on reduction of seizure frequency as a measure of treatment response.

OBJECTIVE: To elucidate rates and predictors of seizure freedom with VNS.

METHODS: We examined 5554 patients from the VNS therapy Patient Outcome Registry, and also performed a systematic review of the literature including 2869 patients across 78 studies.

RESULTS: Registry data revealed a progressive increase over time in seizure freedom after VNS therapy. Overall, 49% of patients responded to VNS therapy 0 to 4 months after implantation (≥50% reduction seizure frequency), with 5.1% of patients becoming seizure-free, while 63% of patients were responders at 24 to 48 months, with 8.2% achieving seizure freedom. On multivariate analysis, seizure freedom was predicted by age of epilepsy onset >12 years (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.38-2.58), and predominantly generalized seizure type (OR, 1.36; 95% CI, 1.01-1.82), while overall response to VNS was predicted by nonlesional epilepsy (OR, 1.38; 95% CI, 1.06-1.81). Systematic literature review results were consistent with the registry analysis: At 0 to 4 months, 40.0% of patients had responded to VNS, with 2.6% becoming seizure-free, while at last follow-up, 60.1% of individuals were responders, with 8.0% achieving seizure freedom.

CONCLUSION: Response and seizure freedom rates increase over time with VNS therapy, although complete seizure freedom is achieved in a small percentage of patients.

 

Approximately 1% of the population has epilepsy, and seizures are refractory to antiepileptic drugs (AEDs) in approximately 30% of these individuals.1 Many patients with drug-resistant temporal or extratemporal lobe epilepsy can become seizure-free with surgical resection or ablation, but other patients with epilepsy are not candidates for resection given the presence of primary generalized seizures, nonlocalizable or multifocal seizure onset, or seizure onset from an eloquent brain region.2-5 Treatments based on neuromodulation, such as vagus nerve stimulation (VNS), have, therefore, become an increasingly important part of multimodal epilepsy treatment. VNS therapy was approved by the US Food and Drug Administration in 1997 as an adjunctive therapy for reducing seizures in patients with medically refractory epilepsy, and more than 80 000 patients have received treatment with VNS.6-8 The efficacy of VNS therapy has been evaluated by randomized controlled trials,9,10 retrospective case series,11,12 meta-analysis,13 and registry-based studies.14 These studies show that about 50% to 60% of patients achieve ≥50% reduction in seizure frequency after 2 years of treatment, and response rates increase over time, likely related to neuromodulatory effects with ongoing stimulation.13 Complete seizure freedom, however, is less common with VNS therapy and other neuromodulation treatment modalities.

Given that a minority of patients achieve seizure freedom with VNS, rates and predictors of seizure freedom have not been well studied and remain poorly understood. The vast majority of studies that evaluate VNS therapy focus on rate of response over time (defined as ≥50% reduction in seizures) and predictors of response; there has never been a large-scale evaluation of seizure freedom as a primary end point in patients treated with VNS. However, seizure freedom is the single best predictor of quality of life in patients with epilepsy,15,16 and therefore a better understanding of seizure freedom rates and predictors in patients treated with VNS therapy is critically needed. Importantly, this information may lead to improved patient selection and counseling in the treatment of drug-resistant epilepsy.

Here, we provide the first large-scale study of VNS therapy with a primary goal of defining seizure freedom rates and predictors, and comparing predictors of seizure freedom with those of overall response to treatment. Our study includes univariate and multivariate analyses of registry data including 5554 patients treated with VNS, and also includes a systematic review of the literature including 2869 patients across 78 studies, to help confirm registry-based results.

Continue —> Rates and Predictors of Seizure Freedom With Vagus Nerve Sti… : Neurosurgery

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[ARTICLE] The adverse event profile of levetiracetam: A meta-analysis on children and adults – Full Text HTML/PDF

Article Outline

  1. 1. Introduction
  2. 2. Methods
    1. 2.1. Criteria for considering studies in this review
      1. 2.1.1. Types of studies
      2. 2.1.2. Types of participants
      3. 2.1.3. Search methods for identification of studies
    2. 2.2. Analysis of adverse events
      1. 2.2.1. Selection of adverse events
      2. 2.2.2. Statistical analysis
  3. 3. Results
    1. 3.1. Included studies
    2. 3.2. General tolerability
    3. 3.3. Treatment withdrawals
    4. 3.4. Adverse effects
    5. 3.5. Dose–effect correlations of statistically significant levetiracetam adverse effects
  4. 4. Discussion
  5. 5. Conclusions
  6. Conflict of interest statement
  7. Appendix A. Supplementary data
  8. References

Highlights

  • We analyzed the adverse events (AEs) profile of levetiracetam with a meta-analysis.
  • A combined analysis of children and adults with any disease was performed.
  • The risk of withdrawals was higher for patients taking levetiracetam than placebo.
  • A general good tolerability profile of levetiracetam has been evidenced.
  • We did not find a clear dose–response relationship for the significant AEs.

Abstract

Purpose: To analyze the adverse events (AEs) significantly associated with levetiracetam (LEV) therapy through a meta-analysis of all available double-blind, randomized placebo-controlled trials (RCTs), performed in any age, gender, ethnic background and disease. General tolerability and study withdrawals due to AEs associated with LEV treatment were also investigated. In addition, a dose–effect responses relationship for all variables was assessed.

Methods: RCTs were identified searching Medline (PubMed), Embase and Cochrane CENTRAL for the words “Levetiracetam” and “randomized controlled trial”, with different search strategies, setting the limits “humans” and “English”. Very common and common AEs according to the summary of product characteristics were investigated. RevMan version 5.2 was used for the statistical analyses. Risk difference with 95% confidence intervals was used to investigate the association of any AEs and withdrawal with LEV.

Results: Twenty-six studies with 2832 patients were included in the RCTs analysis. Nasopharyngitis, somnolence, dizziness, nervousness/irritability and asthenia/fatigue were statistically significant associated with LEV. In addition, LEV was significantly associated with an increased risk of AEs-related withdrawals. No dose–response relationship was found for any of the assessed variables.

Conclusions: This first large meta-analysis suggests that participants were more likely to discontinue LEV than placebo.The AE profile confirmed that LEV is associated with few unfavorable sedative, vestibulocerebellar and behavioral effects, such as nervousness and irritability. However, there does not seem to be a clear dose–response relationship.

Continue —> The adverse event profile of levetiracetam: A meta-analysis on children and adults – Seizure – European Journal of Epilepsy

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