levetiracetam and fosphenytoin

Status epilepticus (SE) is a neurological emergency that can occur in patients with or without epilepsy. Rapid treatment is paramount to mitigate risks of neuronal injury, morbidity/mortality, and healthcare-cost burdens associated with SE. Fosphenytoin is the prodrug of phenytoin designed to enable faster administration and improved tolerability as compared to intravenous (IV) phenytoin in the treatment of SE.. This review evaluates the chemistry, pharmacokinetics, pharmacodynamics, safety, and tolerability of fosphenytoin. Efficacy data for fosphenytoin in the treatment of SE in adults and children are analyzed from initial phase I trials in 1988 through current phase III trials, including the Established Status Epilepticus Treatment Trial (ESETT).. IV phenytoin is an established treatment of SE, but its alkaline aqueous vehicle is associated with dermatologic irritation and systemic complications when rapidly infused. The water-soluble nature of its prodrug, fosphenytoin, allows for rapid infusion, and it is rapidly converted to phenytoin when administered intravenously or intramuscularly. In the ESETT, IV fosphenytoin demonstrated similar efficacy in treatment of established SE when compared to IV levetiracetam and IV valproate in adults and children, making it a reasonable choice in the treatment of SE that is unresponsive to benzodiazepines.

Topics: Adult; Anticonvulsants; Child; Humans; Levetiracetam; Phenytoin; Status Epilepticus

To synthesize the available evidence examining the efficacy and safety of levetiracetam compared with phenytoin or fosphenytoin in benzodiazepine-refractory pediatric status epilepticus.. We searched (from inception until April 27, 2020) Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials.. Two reviewers, independently and in duplicate, screened citations and manuscripts for eligible randomized controlled trials.. Independently and in duplicate, we performed data abstraction, risk of bias assessment, and certainty assessment using Grading of Recommendations, Assessment, Development, and Evaluation. We performed meta-analyses using random-effect models or, if insufficient data, presented findings narratively.. We identified seven randomized controlled trials (n = 1,575). Pooled analysis demonstrated low certainty evidence for no difference of levetiracetam on time to seizure cessation (mean difference, -3.11 min; 95% CI, -6.67 to 0.45), early seizure cessation (relative risk, 1.09, 95% CI, 0.95-1.26), or late seizure cessation (relative risk, 1.05; 95% CI, 0.93-1.18). Adverse event outcomes were limited by low event numbers. We found low certainty evidence for less respiratory depression with levetiracetam (relative risk, 0.28; 95% CI, 0.12-0.69).. The efficacy of levetiracetam is comparable with phenytoin or fosphenytoin in children with benzodiazepine-refractory status epilepticus (low certainty evidence). Levetiracetam may cause less respiratory depression. Clinicians and guideline developers should weigh safety profiles when choosing between these agents.

Topics: Anticonvulsants; Child; Humans; Levetiracetam; Phenytoin; Status Epilepticus

Compare the cost and effectiveness of nonbenzodiazepine antiepileptic drugs (non-BZD AEDs) for treatment of BZD-resistant convulsive status epilepticus (SE).. Decision analysis model populated with effectiveness data from a systematic review and meta-analysis of the literature, and cost data from publicly available prices. The primary outcome was cost per seizure stopped ($/SS). Sensitivity analyses evaluated the robustness of the results across a wide variation of the input parameters.. VPA and PB were more effective than PHT for SE. There is substantial overlap in the cost-effectiveness of non-BZD AEDs for SE, but available evidence does not support the preeminence of PHT, neither in terms of effectiveness nor in terms of cost-effectiveness.

Topics: Anticonvulsants; Benzodiazepines; Cost-Benefit Analysis; Decision Support Techniques; Humans; Lacosamide; Levetiracetam; Phenobarbital; Phenytoin; Status Epilepticus; Treatment Failure; Valproic Acid

In this review study, second-generation antiepileptic drugs (AEDs) (levetiracetam, gabapentin, topiramate, lamotrigine, zonisamide, oxcarbazepine, vigabatrin, pregabalin, rufinamide, tiagabine, lacosamide, and felbamate) and injectable AEDs (levetiracetam, lacosamide, fosphenytoin, lorazepam, and valproic acid) available in North America were compared with those available in Japan. Three second-generation AEDs (gabapentin, topiramate, and lamotrigine) were recently approved in Japan. Levetiracetam is currently under review for approval by the Japanese regulatory agency. An ideal AED would have a broad-spectrum activity to control multiple types of seizures, favorable safety profile, limited potential for drug-drug interaction, many bioequivalent formulations, long half life to allow infrequent administration, and antiepileptogenic effects that may provide a fundamental cure of epileptic patients by suppressing the development of epileptogenic network and neutralizing previously established epileptogenic foci in the brain. The second-generation AEDs have been developed to possess some of these ideal properties. All the second-generation AEDs are efficacious for the treatment of patients with partial seizures. In addition, levetiracetam, topiramate, lamotrigine, and zonisamide are effective for the treatment of patients with generalized tonic-clonic seizures, absences, myoclonic seizures, Lennox-Gastaut syndrome, and West syndrome; however, lamotrigine is not effective for the treatment of patients with myoclonic seizures. Rufinamide and felbamate are useful for the treatment of patients with Lennox-Gastaut syndrome; however owing to its serious adverse effects, including aplastic anemia and hepatic failure, felbamate is used as the last resort for the treatment of patients with intractable seizures. Vigabatrin is particularly effective for the treatment of patients with West syndrome; however, the patients need to be regularly monitored for the development of peripheral visual field defect. Gabapentin, oxcarbazepine, vigabatrin, and tiagabine are ineffective for the treatment of patients with absences and/or myoclonic seizures and may aggravate these conditions. Treatment with levetiracetam or topiramate (off-label use) is the new option for patients with refractory status epilepticus, which is characterized by downregulation of the inhibitory gamma-aminobutyric acid system, because these drugs act via different mechanisms and are rapidly titratable, espec

Topics: Anticonvulsants; Carbamazepine; Drug Approval; Fructose; Humans; Japan; Lamotrigine; Levetiracetam; Lorazepam; North America; Phenytoin; Piracetam; Topiramate; Triazines

Topics: Anticonvulsants; Benzodiazepines; Humans; Levetiracetam; Phenobarbital; Phenytoin; Piracetam; Prodrugs; Status Epilepticus; Treatment Outcome; Valproic Acid

Topics: Anticonvulsants; Epilepsy; Humans; Infusions, Intravenous; Injections, Intravenous; Levetiracetam; Pharmaceutical Vehicles; Phenytoin; Piracetam; Solubility; Valproic Acid

The introduction of these new antiepileptic drugs, from felbamate to levetiracetam, raised hope of control of epilepsy with fewer adverse effects and improved quality of life. Unfortunately, many patients continue to experience refractory epilepsy despite the use of these new agents, and dose-related adverse effects and idiosyncratic reactions continue to be problematic. A recent report describes six new compounds in preclinical development, and five in clinical trials [131]. As the number of available, effective, but imperfect antiepileptic drugs increases, many challenges remain. These include: choosing the drug appropriate for the epileptic syndrome, assessing accurately the range of a drug's adverse effects in an individual patient, and considering carefully the drug's interactions in combination drug therapy. In considering drug combinations, differing mechanisms of drug action and favorable pharmacodynamic interactions (an area requiring additional studies) are of importance. Clinicians caring for children who have epilepsy anticipate further advances in the pharmacogenetics and molecular pathophysiology of epilepsy, leading to individually tailored, effective, and safe therapy.

Topics: Acetates; Amines; Anticonvulsants; Carbamazepine; Child; Cyclohexanecarboxylic Acids; Dioxolanes; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Nipecotic Acids; Oxcarbazepine; Phenylcarbamates; Phenytoin; Piracetam; Propylene Glycols; Thiazines; Tiagabine; Topiramate; Triazines; Vigabatrin; Zonisamide

Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is crucial. Although fosphenytoin (FPHT) is recommended as a second-line treatment, levetiracetam (LEV) reportedly has similar efficacy, but higher safety. Therefore, we herein compared LEV with FPHT in adult SE.. We initiated a multicentre randomised control trial in emergency departments with adult patients with convulsive SE. Diazepam was initially administered, followed intravenously by FPHT at 22.5 mg/kg or LEV at 1000-3000 mg. The primary outcome was assigned as the seizure cessation rate within 30 min of the administration of the study drug.. A total of 176 adult patients with SE were enrolled (82 FPHT and 94 LEV), and 3 were excluded from the full analysis set. Seizure cessation rates within 30 min were 83.8% (67/80) in the FPHT group and 89.2% (83/93) in the LEV group. The difference in these rates was 5.5% (95% CI -4.7 to 15.7, p=0.29). The non-inferiority of LEV to FPHT was confirmed with p<0.001 by the Farrington-Manning test. No significant differences were observed in the seizure recurrence rate or intubation rate within 24 hours. Serious adverse events developed in three patients in the FPHT group and none in the LEV group (p=0.061).. The efficacy of LEV was similar to that of FPHT for adult SE following the administration of diazepam. LEV may be recommended as a second-line treatment for SE along with phenytoin/FPHT.. jRCTs031190160.

Topics: Adult; Anticonvulsants; Diazepam; Humans; Levetiracetam; Phenytoin; Seizures; Status Epilepticus; Treatment Outcome

We describe a subset of patients with toxin-related precipitants of seizures/status epilepticus enrolled in the Established Status Epilepticus Treatment Trial (ESETT).. The ESETT was a prospective, double-blinded, adaptive trial evaluating levetiracetam, valproate, and fosphenytoin as second-line agents in benzodiazepine-refractory status epilepticus in adults and children. The primary outcome was the absence of seizures and improvement in the level of consciousness 1 hour after study drug administration. In this post hoc analysis, the safety and efficacy of second-line agents in a subset of patients with toxin-related seizures are described.. A total of 249 adults and 229 children were enrolled in the ESETT. Toxin-related seizures occurred in 29 (11.6%) adults and 1 child (0.4%). In adults, men were more likely to have toxin-related seizures than women (25 of 145, 17.2% versus 4 of 104, 3.9%). The most common toxin-related precipitants were alcohol withdrawal and cocaine, 11(37%) of 30 patients each. Cocaine was used with other substances by most patients 10 (91%) of 11, most commonly with an opioid 7 (64%) of 11. For alcohol withdrawal-related seizures, treatment successes with levetiracetam, valproate, and fosphenytoin were 3 (100%) of 3, 3 (50%) of 6, and 1 (50%) of 2, respectively. For cocaine-related seizures, treatment success was 1 (14%) of 7 for levetiracetam, 0 (0%) of 1 for valproate, and 1 (33%) of 3 for fosphenytoin. One patient who used cocaine and an opioid received fosphenytoin and developed life-threatening hypotension.. In the ESETT, approximately 1 in 10 adult patients with status epilepticus presented with a toxin-related seizure. Alcohol withdrawal and cocaine/opioid use were the most common toxin-related precipitants. Toxin-related benzodiazepine-refractory status epilepticus was successfully treated with a single dose of second-line antiseizure medication in 42% of the patients.

Topics: Adult; Alcoholism; Analgesics, Opioid; Anticonvulsants; Benzodiazepines; Child; Cocaine; Female; Humans; Levetiracetam; Male; Phenytoin; Prospective Studies; Seizures; Status Epilepticus; Substance Withdrawal Syndrome; Valproic Acid

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 μg/mL for LEV, 11.3 to 26.7 μg/mL for PHT and 126 to 223 μg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.

Topics: Anticonvulsants; Benzodiazepines; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Levetiracetam; Male; Phenytoin; Protein Binding; Status Epilepticus; Valproic Acid

Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is important. Phenytoin and fosphenytoin, the prodrug of phenytoin with less severe adverse effects, have been recommended as second-line treatments. However, fosphenytoin causes severe adverse events, such as hypotension and arrhythmia. Levetiracetam reportedly has similar efficacy and higher safety for SE; however, evidence to support its use for adult SE is lacking. In the present study, a non-inferiority designed multicenter randomized controlled trial (RCT) is being conducted to compare levetiracetam with fosphenytoin after diazepam as a second-line treatment for SE.. This multicenter, prospective, and open-label RCT is conducted in emergency departments. Between December 23, 2019, and March 31, 2023, 176 patients with convulsive SE transported to an emergency room will be randomized into a fosphenytoin group and levetiracetam group at a ratio of 1:1. The definition of SE is "continuous seizures longer than 5 min or discrete seizures longer than 2 min with intervening consciousness disturbance." In both groups, diazepam is initially administered at 1-20 mg, followed by intravenous fosphenytoin at 22.5 mg/kg or intravenous levetiracetam at 1000-3000 mg. The primary outcome is the seizure cessation rate within 30 min. Seizure recurrence within 24 h, severe adverse events, and intubation rate within 24 h are secondary outcomes.. The present study was approved and conducted as an initiative study of the Japanese Association for Acute Medicine. If non-inferiority is identified, the society will pursue an application for the national health insurance coverage of levetiracetam for SE via a public knowledge-based application.. Japan Registry of Clinical Trials jRCTs031190160 . Registered on December 13, 2019.

Topics: Adult; Anticonvulsants; Diazepam; Humans; Japan; Levetiracetam; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Phenytoin; Randomized Controlled Trials as Topic; Status Epilepticus; Treatment Outcome

To determine whether levetiracetam is an alternative to fosphenytoin to control Benzodiazepine Refractory Status Epilepticus (BRSE) in pediatric population and also to compare the acute drug related side-effects and ventilation requirement among the both arms of anti-epileptic drug therapy.. All consecutive children admitted with BRSE were randomized to group A, who received fosphenytoin at 20 mg/kg phenytoin equivalents (PE) dose and group B who received levetiracetam at 40 mg/kg over 10 min. Time to terminate seizure (response latency) was measured. If seizure remained refractory after 20 min of test drug administration, appropriate drug escalation was made according to pediatrician's discretion. All primary and secondary outcome measures were compared between the two therapeutic groups.. Of 61 children enrolled over 18 mo period, 29 (47.5%) were randomized to group A and 32 (52.5%) were randomized to Group B. Baseline characteristics were comparable between the two groups. Among 61 children, 58(98%) required Pediatric Intensive Care Unit (PICU) admission and among those 5(8.2%) children required mechanical ventilation. Duration of PICU stay, hospital stay, the response latency and seizure recurrence were compared between both groups. Significant number of children received additional anti-epileptic drugs (AEDs) in fosphenytoin group [9/29(31%)] compared to levetiracetam group [2/32(7%)] to control seizure.. Levetiracetam may be an effective alternative to fosphenytoin in management of BRSE in children but multicentric trials with large sample size are needed to substantiate this observation.

Topics: Anticonvulsants; Benzodiazepines; Child; Humans; Levetiracetam; Neoplasm Recurrence, Local; Phenytoin; Status Epilepticus; Treatment Outcome

Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups.. In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075.. Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group.. Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus.. National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Topics: Adolescent; Adult; Age Distribution; Age Factors; Aged; Aged, 80 and over; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Infant; Levetiracetam; Male; Middle Aged; Phenytoin; Status Epilepticus; Valproic Acid; Young Adult

The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.

Topics: Adolescent; Adult; Anticonvulsants; Body Weight; Dose-Response Relationship, Drug; Female; Humans; Levetiracetam; Male; Phenytoin; Single-Blind Method; Status Epilepticus; Treatment Outcome; Valproic Acid; Young Adult

The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied.. In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death.. A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant.. In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).

Topics: Adolescent; Adult; Anticonvulsants; Benzodiazepines; Child; Child, Preschool; Double-Blind Method; Drug Resistance; Female; Humans; Hypotension; Infusions, Intravenous; Injections, Intramuscular; Levetiracetam; Male; Middle Aged; Phenytoin; Status Epilepticus; Valproic Acid; Young Adult

We present a novel Bayesian adaptive comparative effectiveness trial comparing three treatments for status epilepticus that uses adaptive randomization with potential early stopping.. The trial will enroll 720 unique patients in emergency departments and uses a Bayesian adaptive design.. The trial design is compared to a trial without adaptive randomization and produces an efficient trial in which a higher proportion of patients are likely to be randomized to the most effective treatment arm while generally using fewer total patients and offers higher power than an analogous trial with fixed randomization when identifying a superior treatment.. When one treatment is superior to the other two, the trial design provides better patient care, higher power, and a lower expected sample size.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Bayes Theorem; Child; Child, Preschool; Comparative Effectiveness Research; Early Termination of Clinical Trials; Emergency Service, Hospital; Humans; Intention to Treat Analysis; Levetiracetam; Middle Aged; Models, Statistical; Phenytoin; Piracetam; Randomized Controlled Trials as Topic; Research Design; Status Epilepticus; Treatment Outcome; Valproic Acid; Young Adult

Benzodiazepine-refractory status epilepticus (established status epilepticus, ESE) is a relatively common emergency condition with several widely used treatments. There are no controlled, randomized, blinded clinical trials to compare the efficacy and tolerability of currently available treatments for ESE. The ESE treatment trial is designed to determine the most effective and/or the least effective treatment of ESE among patients older than 2 years by comparing three arms: fosphenytoin (fPHT) levetiracetam (LVT), and valproic acid (VPA). This is a multicenter, randomized, double-blind, Bayesian adaptive, phase III comparative effectiveness trial. Up to 795 patients will be randomized initially 1:1:1, and response-adaptive randomization will occur after 300 patients have been recruited. Randomization will be stratified by three age groups, 2-18, 19-65, and 66 and older. The primary outcome measure is cessation of clinical seizure activity and improving mental status, without serious adverse effects or further intervention at 60 min after administration of study drug. Each subject will be followed until discharge or 30 days from enrollment. This trial will include interim analyses for early success and futility. This trial will be considered a success if the probability that a treatment is the most effective is >0.975 or the probability that a treatment is the least effective is >0.975 for any treatment. Proposed total sample size is 795, which provides 90% power to identify the most effective and/or the least effective treatment when one treatment arm has a true response rate of 65% and the true response rate is 50% in the other two arms.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Child; Child, Preschool; Double-Blind Method; Humans; Levetiracetam; Middle Aged; Phenytoin; Piracetam; Research Design; Status Epilepticus; Treatment Outcome; Valproic Acid; Young Adult

Topics: Anticonvulsants; Benzodiazepines; Child; Humans; Levetiracetam; Phenytoin; Status Epilepticus

Topics: Benzodiazepines; Humans; Levetiracetam; Phenytoin; Status Epilepticus; Treatment Outcome

Topics: Anticonvulsants; Child; Double-Blind Method; Humans; Levetiracetam; Phenytoin; Status Epilepticus; Valproic Acid

Multiple recent instances of nerve agent (NA) exposure in civilian populations have occurred, resulting in a variety of negative effects and lethality in both adult and pediatric populations. Seizures are a prominent effect of NAs that can result in neurological damage and contribute to their lethality. Current anticonvulsant treatments for NAs are approved for adults, but no approved pediatric treatments exist. Further, the vast majority of NA-related research in animals has been conducted in adult male subjects. There is a need for research that includes female and pediatric populations in testing. In this project, adult and pediatric male and female rats were challenged with sarin or VX and then treated with fosphenytoin, levetiracetam, or propofol. In this study, fosphenytoin and levetiracetam failed to terminate seizure activity when animals were treated 5 min after seizure onset. Propofol was effective, exhibiting high efficacy and potency for terminating seizure activity quickly in pediatric and adult animals, suggesting it may be an effective anticonvulsant for NA-induced seizures in pediatric populations.

Topics: Age Factors; Animals; Anticonvulsants; Brain; Disease Models, Animal; Female; Levetiracetam; Male; Organothiophosphorus Compounds; Phenytoin; Propofol; Rats, Sprague-Dawley; Sarin; Sex Factors; Status Epilepticus

Topics: Benzodiazepines; Humans; Levetiracetam; Phenytoin; Status Epilepticus; Treatment Outcome

Topics: Adult; Anticonvulsants; Disease Management; Drug Therapy, Combination; Epilepsy, Generalized; Female; Humans; Levetiracetam; Midazolam; Phenytoin; Status Epilepticus; Valproic Acid

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are immune-mediated diseases characterized by an extensive loss of the epidermal skin layer, often resulting in death. SJS and TEN are often triggered by certain drugs, including antiepileptic drugs (AEDs). Epilepsy is very difficult to treat and often involves the combination of two or more AEDs. In this study, we quantified not only the risk of SJS or TEN associated with single-AED therapy but also the risk related to concomitant AED treatment using reporting-derived signals.. An analysis of the Japanese Adverse Drug Event Report (JADER) database was performed from the first quarter of 2004 to the fourth quarter of 2018. The single-AED signals were evaluated using the proportional reporting ratio (PRR), and the combination therapy signals were evaluated using Ω shrinkage measure and combination risk ratio (CRR).. SJS signals were associated with 11 AEDs, and TEN signals were related to 12 AEDs. Moreover, the following AED combinations were associated with SJS signals: carbamazepine-lorazepam (Ω. This study identified two AED combinations that increased the SJS signals and seven combinations that increased the TEN signals. Although AED monotherapies require attention for SJS and TEN, some AED combinations require extra caution.

Topics: Anticonvulsants; Carbamazepine; Clobazam; Clonazepam; Databases, Factual; Drug Therapy, Combination; Epilepsy; Gabapentin; Humans; Japan; Lacosamide; Lamotrigine; Levetiracetam; Lorazepam; Pharmacovigilance; Phenytoin; Stevens-Johnson Syndrome; Valproic Acid

To identify factors associated with low benzodiazepine (BZD) dosing in patients with refractory status epilepticus (RSE) and to assess the impact of BZD treatment variability on seizure cessation.. This was a retrospective study with prospectively collected data of children with convulsive RSE admitted between June 2011 and January 2019. We analyzed the initial and total BZD dose within 10 minutes of treatment initiation. We used logistic regression modeling to evaluate predictors of low BZD dosing and multivariate Cox regression analysis to assess the impact of low BZD dosing on time to seizure cessation.. We included 289 patients (55.7% male) with a median age of 4.3 (1.3-9.5) years. BZDs were the initial medication in 278 (96.2%). Of those, 161 patients (57.9%) received a low initial dose. Low initial BZD doses occurred in both out-of-hospital (57 of 106; 53.8%) and in-hospital (104 of 172; 60.5%) settings. One hundred three patients (37.1%) received low total BZD dose. Male sex (odds ratio [OR] 2, 95% confidence interval [CI] 1.18-3.49;. BZD doses were lower than recommended in both out-of-hospital and in-hospital settings. Factors associated with low total BZD dose included male sex, older age, no prior epilepsy diagnosis, and delayed BZD treatment. Low total BZD dosing was associated with decreased likelihood of Seizure cessation.. This study provides Class III evidence that patients with RSE who present with male sex, older age, no prior diagnosis of epilepsy, and delayed BZD treatment are more likely to receive low total BZD doses. This study provides Class III evidence that in pediatric RSE low total BZD dose decreases the likelihood of seizure cessation.

Topics: Adolescent; Age Factors; Anticonvulsants; Benzodiazepines; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Resistant Epilepsy; Female; Guideline Adherence; Humans; Infant; Levetiracetam; Male; Multivariate Analysis; Phenobarbital; Phenytoin; Practice Guidelines as Topic; Proportional Hazards Models; Retrospective Studies; Sex Factors; Status Epilepticus; Time-to-Treatment

Thermoregulatory derangements secondary to valproic acid (VPA) administration, specifically hypothermia, have been reported throughout the literature, but a handful of times. This case report describes a 28-year-old male presenting status-post multiple tonic-clonic seizures, treated for persistent seizure activity refractory to benzodiazepines with valproic acid (VPA), levetiracetam, and fosphenytoin. After just over an hour, the patient's core temperature fell from 36.8 °C to 34.9 °C. Temperatures were repeated for confirmation, no further doses of VPA were administered, and the patient's temperature returned to normal over the next 7 h with the use of warming blankets. Levetiracetam and fosphenytoin were continued with no further reported development of hypothermia during the patient's admission. After reviewing other potential causes, a thorough drug database review was performed that found VPA to be the only medication administered with published reports of inducing hypothermia. The mechanism of thermoregulatory derangement associated with VPA is not clearly defined and much of the evidence surrounds alterations in gamma-aminobutyric acid (GABA) activity in animal studies. To our knowledge, this case report is the first reported case of VPA-induced hypothermia following a single dose in the emergency department and offers the potential that prompt return to normothermia is likely following discontinuation of the offending agent.

Topics: Adult; Anticonvulsants; Humans; Hypothermia; Levetiracetam; Male; Phenytoin; Seizures; Valproic Acid

Benzodiazepines are used as first-line treatments for status epilepticus. Fosphenytoin (FPHT) is recommended for second-line therapy; however, intravenous injection of levetiracetam (LEV) may also be effective against status epilepticus. Herein, we compared the efficacy and safety of LEV as a second-line treatment for status epilepticus with FPHT in Japanese patients.Patients with status epilepticus were selected from the database of the Emergency and Critical Care Center of Hitachi General Hospital. The subjects were patients whose status epilepticus was successfully stopped by diazepam, and in whom FPHT or LEV was administered after diazepam. As LEV injections recently became clinically available in Japan, the choice of drug was determined by the treatment period. Thus, 21 patients who were intravenously injected with LEV as a second-line therapy and 42 matched patients (historical controls) who were treated with FPHT (1:2) were selected.The subjects had a mean age of 64.0 ± 2.2 years, and included 48 males and 15 females. The status epilepticus control rates of the FPHT and LEV groups did not differ significantly (81.0% [34/42] vs 85.1% [18/21], respectively; P  =  .69). As for serious adverse events, a reduction in blood pressure was observed in the FPHT group, but not in the LEV group. The oral anticonvulsant switching rates of the 2 groups were similar, but the same-drug switching rates of the FPHT and LEV groups were 8.1% and 77.8%, respectively.The efficacy of intravenous LEV injections after status epilepticus was equivalent to that of FPHT, and the incidence of adverse events was lower in the LEV group. LEV is effective and safe at preventing recurrent seizures after status epilepticus following benzodiazepine treatment.

Topics: Administration, Intravenous; Administration, Oral; Anticonvulsants; Blood Pressure; Databases, Factual; Diazepam; Drug Substitution; Emergency Medical Services; Female; Hospitals, General; Humans; Japan; Levetiracetam; Male; Middle Aged; Phenytoin; Piracetam; Recurrence; Retrospective Studies; Seizures; Status Epilepticus; Treatment Outcome

Early seizures after severe traumatic brain injury (TBI) have a reported incidence of up to 15 %. Prophylaxis for early seizures using 1 week of phenytoin is considered standard of care for seizure prevention. However, many centers have substituted the anticonvulsant levetiracetam without good data on the efficacy of this approach. Our hypothesis was that the treatment with levetiracetam is not effective in preventing early post-traumatic seizures.. All trauma patients sustaining a TBI from January 2007 to December 2009 at an urban level-one trauma center were retrospectively analyzed. Seizures were identified from a prospectively gathered morbidity database and anticonvulsant use from the pharmacy database. Statistical comparisons were made by Chi square, t tests, and logistic regression modeling. Patients who received levetiracetam prophylaxis were matched 1:1 using propensity score matching with those who did not receive the drug.. 5551 trauma patients suffered a TBI during the study period, with an overall seizure rate of 0.7 % (39/5551). Of the total population, 1795 were diagnosed with severe TBI (Head AIS score 3-5). Seizures were 25 times more likely in the severe TBI group than in the non-severe group [2.0 % (36/1795) vs. 0.08 % (3/3756); OR 25.6; 95 % CI 7.8-83.2; p < 0.0001]. Of the patients who had seizures after severe TBI, 25 % (9/36) received pharmacologic prophylaxis with levetiracetam, phenytoin, or fosphenytoin. In a matched cohort by propensity scores, no difference was seen in seizure rates between the levetiracetam group and no-prophylaxis group (1.9 vs. 3.4 %, p = 0.50).. In this propensity score-matched cohort analysis, levetiracetam prophylaxis was ineffective in preventing seizures as the rate of seizures was similar whether patients did or did not receive the drug. The incidence of post-traumatic seizures in severe TBI patients was only 2.0 % in this study; therefore we question the benefit of routine prophylactic anticonvulsant therapy in patients with TBI.

Topics: Adolescent; Adult; Anticonvulsants; Brain Injuries, Traumatic; Chemoprevention; Databases, Factual; Female; Humans; Levetiracetam; Male; Middle Aged; Phenytoin; Piracetam; Propensity Score; Retrospective Studies; Seizures; Treatment Failure; Young Adult

Seizure prophylaxis is used in a variety of conditions, including supratentorial intracranial hemorrhage (ICH). In adults, studies have demonstrated phenytoin as the drug of choice for seizure prophylaxis; in children, levetiracetam is often provided due to its favorable side effect profile and pharmacokinetics. This study evaluated the difference in efficacy between these treatment options.. This retrospective review included 126 patients between 1 month and 17 years of age with acute supratentorial ICH; all received seizure prophylaxis. Demographic data and outcome assessments were compared.. Seizure prophylaxis was provided with (fos)phenytoin in 40 children, levetiracetam in 61 children, and both drugs in 25 patients. Baseline characteristics of the treatment groups were similar, except that more patients treated with (fos)phenytoin had seizures on presentation. Patients treated solely with (fos)phenytoin had a higher probability of early seizures (within 7 days of ICH) compared with those treated only with LVT, controlling for relevant variables including seizures on presentation (OR 24.6, p = 0.002). Patients treated with (fos)phenytoin were more likely to need additional antiepileptic drugs for seizure control (p = 0.005). There was no significant difference in the incidence of late seizures (> 7 days after ICH) (p = 0.265). Adverse events necessitating a change in therapy were uncommon.. Levetiracetam is a reasonable alternative to (fos)phenytoin for prophylaxis of early posthemorrhagic seizures. Levetiracetam and (fos)phenytoin are well tolerated in children. Prospective studies are needed to determine superiority, optimal dosing, and impact on long-term outcomes.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Female; Humans; Incidence; Infant; Intracranial Hemorrhages; Levetiracetam; Male; Phenytoin; Piracetam; Primary Prevention; Retrospective Studies; Seizures; Treatment Outcome

Prophylactic antiseizure drugs (PAD) are commonly prescribed for non-traumatic intracerebral hemorrhage (ICH) despite limited evidence for this indication. We sought to determine the current prescribing patterns of the use of a PAD for ICH.. A 36-item survey was distributed to physicians who manage ICH patients soliciting details of PAD prescription in their practice.. A total of 199 physicians responded to the survey, all of who manage 50 or more ICH patients per year. The respondents were neurologists (32%), neurosurgeons (11%), and intensivists (57%) in academia (69%) and private practice (31%). Prophylactic antiseizure drugs prescriptions used: never (33%), 1-33% (35%), 34-66% (14%), 67-99% (9%) of the time, or always (9%). Most respondents performed electroencephalographic and serum level monitoring in at least some patients. Levetiracetam was used most often (60%), followed by fosphenytoin (37%), for a usual duration of days (36%), weeks (47%), or months (17%). Prophylactic antiseizure drugs prescription varied by patient characteristics and physician specialty. Perception of physician community consensus regarding PAD use for ICH among respondents ranged from strongly (7%) or weakly (23%) against the practice, to a fairly equal division of opinion (41%), to weakly (27%) or strongly (4%) in favor of the practice.. We found variability of multiple aspects of the current prescribing patterns and opinions regarding the use of a PAD for ICH. This variability is likely secondary to insufficient data. Clinical equipoise exists for this issue, and controlled trials would be both justified and useful.

Topics: Anticonvulsants; Brain; Cerebral Hemorrhage; Drug Prescriptions; Drug Utilization; Electroencephalography; Humans; Levetiracetam; Phenytoin; Piracetam; Practice Patterns, Physicians'; Seizures; Surveys and Questionnaires

As part of the development of the Neurocritical Care Society (NCS) Status Epilepticus (SE) Guidelines, the NCS SE Writing Committee conducted an international survey of SE experts.. The survey consisted of three patient vignettes (case 1, an adult; case 2, an adolescent; case 3, a child) and questions regarding treatment. The questions for each case focused on initial and sequential therapy as well as when to use continuous intravenous (cIV) therapy and for what duration. Responses were obtained from 60/120 (50%) of those surveyed.. This survey reveals that there is expert consensus for using intravenous lorazepam for the emergent (first-line) therapy of SE in children and adults. For urgent (second-line) therapy, the most common agents chosen were phenytoin/fosphenytoin, valproate sodium, and levetiracetam; these choices varied by the patient age in the case scenarios. Physicians who care for adult patients chose cIV therapy for RSE, especially midazolam and propofol, rather than a standard AED sooner than those who care for children; and in children, there is a reluctance to choose propofol. Pentobarbital was chosen later in the therapy for all ages.. There is close agreement between the recently published NCS guideline for SE and this survey of experts in the treatment of SE.

Topics: Administration, Intravenous; Adult; Anticonvulsants; Child; Consensus; Expert Testimony; Humans; Hypnotics and Sedatives; Levetiracetam; Lorazepam; Midazolam; Pentobarbital; Phenytoin; Piracetam; Propofol; Societies, Medical; Status Epilepticus; Surveys and Questionnaires; Valproic Acid

Continuous electroencephalography (cEEG) is increasingly used to detect both clinical and subclinical seizures in patients with traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH). We assess whether EEG findings predict outcomes in TBI/SAH patients enrolled in a levetiracetam (LEV) vs. fosphenytoin (fos-PHT) seizure prevention trial (NCT00618436). This prospective, single-blinded, comparative trial randomized 52 patients with TBI or SAH to receive prophylactic LEV or fos-PHT. Continuous video EEG monitoring was conducted for the initial 72 h of medication administration. The association between EEG findings (degree of generalized and focal slowing, presence and frequency of epileptiform discharges and seizures) and outcomes (Glasgow Outcomes Scale-Extended (GOS-E) and Disability Rating Scale (DRS)) at discharge, 3 and 6 months was assessed using a generalized linear model. Severity of generalized slowing tended to be associated with outcomes in both treatment groups (discharge DRS, p=0.042; discharge GOS-E, p=0.026; 3 month DRS, p=0.051). The presence of focal slowing, the presence and frequency of epileptiform discharges and the presence of seizures were not predictive of outcome in either treatment group (all p>0.15). While it has been shown that LEV is associated with better outcome than fos-PHT when used as seizure prophylaxis in brain injury, aside from severity of generalized slowing, electrographic findings of focal slowing, epileptiform discharges, and seizures were not themselves associated with outcomes in patients with TBI or SAH enrolled in a randomized clinical trial.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Brain Injuries; Disability Evaluation; Electroencephalography; Female; Glasgow Outcome Scale; Humans; Levetiracetam; Linear Models; Male; Middle Aged; Phenytoin; Piracetam; Randomized Controlled Trials as Topic; Seizures; Statistics, Nonparametric; Subarachnoid Hemorrhage; Young Adult

Anti-seizure prophylaxis is routinely utilized during busulfan administration for HSCT. We evaluated the feasibility and efficacy of levetiracetam in children undergoing HSCT. A total of 28 children and young adults received levetiracetam during HSCT and the outcomes and costs were compared to a historical, but similar cohort of 25 patients who had received fosphenytoin. Levetiracetam was well tolerated and was efficacious in preventing seizures. Cost of drug, administration, and monitoring were also similar among the two groups. Due to non-induction of the hepatic cytochrome P450 enzymes, levetiracetam may lead to better dose assurance of busulfan in targeted dose regimens for HSCT.

Topics: Adolescent; Adult; Anticonvulsants; Busulfan; Child; Child, Preschool; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Levetiracetam; Phenytoin; Piracetam; Seizures; Transplantation Conditioning; Young Adult

To study the incidence and extent of the occasionally noted hypotension after intravenous (IV) infusions of fosphenytoin (FOS) and levetiracetam (LEV) in patients presenting with acute cerebral symptoms.. Retrospective data collection of consecutive patients with acute cerebral symptoms who received IV infusions of a single dose of 750 mg or more of either fosphenytoin or levetiracetam and had documented blood pressure values in the 2h prior and the 2h after their IV infusion.. More than 10 mmHg drop in the systolic, diastolic and MBP was observed in the FOS group following the IV infusion (-16.82 mmHg, -11.60 mmHg, and 13.34 mmHg, respectively). However, there was not a significant change in the MBP after LEV infusion (1.54 mmHg, 1.84 mmHg, and 1.74 mmHg for systolic, diastolic and MBP change, respectively). The difference in the systolic, diastolic and MBP changes between the two groups was statistical significant (all p values are <0.0001) after adjusting for age, clinical presentations of the patients and if they were on any antihypertensive medication in the hospital. Sixty two percent of patients who received FOS had >10 mmHg decrease in their MBP. In the LEV group, only 2 of the 50 patients (4%) had >10 mmHg decrease in their MBP. The difference in proportion of the patients with >10 mmHg drop in MBP between the two study groups is also statistically significant (p<0.001) for age, clinical presentations of the patients and if they were on any antihypertensive medication in the hospital.. IV infusion of FOS in subjects presenting with acute cerebral symptoms may cause significant decreases in their blood pressure. This was not seen in patients receiving IV LEV infusions. Since maintaining adequate cerebral perfusion pressure is a key point in the management of patients with acute cerebral symptoms, the results of this study may carry a clinical impact on the management of this subgroup of patients.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Chi-Square Distribution; Female; Humans; Hypotension; Levetiracetam; Male; Medical Records; Middle Aged; Patient Selection; Phenytoin; Piracetam; Regression Analysis; Retrospective Studies; Seizures; Treatment Outcome

We evaluated the anticonvulsant efficacy of the new antiepileptic drugs (AEDs) gabapentin and levetiracetam in amygdala kindled rats that had been preselected with respect to their response to phenytoin. Anticonvulsant response was tested by determining the afterdischarge threshold (ADT), i.e. a sensitive measure for drug effects on focal seizure activity. By repeated testing with the phenytoin prodrug fosphenytoin, three groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (phenytoin responders), rats which showed no anticonvulsant response (phenytoin nonresponders), and rats with variable responses (variable phenytoin responders). The latter, largest group was used to evaluate at which doses gabapentin and levetiracetam exerted significant anticonvulsant effects on ADT 1 h after i.p. drug administration. Effective doses were then used for drug testing in phenytoin responders and nonresponders. Both gabapentin and levetiracetam proved to be effective anticonvulsant drugs in the kindling model by significantly increasing the ADT. In addition, both drugs markedly decreased seizure severity recorded at ADT currents, indicating that these drugs affect seizure threshold in the epileptic focus and seizure spread from the focus in the kindling model. When the threshold for secondary generalized seizures (GST) was determined in addition to ADT, gabapentin and levetiracetam strikingly increased this threshold compared to predrug control. In phenytoin nonresponders, gabapentin and levetiracetam significantly increased ADT and GST, which is in line with their proven efficacy in patients with refractory partial epilepsy in whom older AEDs have failed. In phenytoin responders, gabapentin tended to be more efficacious in increasing ADT and GST than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. In contrast to gabapentin, levetiracetam was more efficacious in increasing ADT in nonresponders than in responders. The data of this study substantiate that phenytoin nonresponders are a unique model for the search of new AEDs with improved efficacy in refractory partial epilepsy.

Topics: Acetates; Amines; Animals; Anticonvulsants; Cyclohexanecarboxylic Acids; Drug Evaluation; Drug Resistance; Female; Gabapentin; gamma-Aminobutyric Acid; Kindling, Neurologic; Levetiracetam; Phenytoin; Piracetam; Rats; Rats, Wistar; Seizures