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Abstract Sex differences in drug pharmacokinetics include variations in the expression of the cytochrome P450 enzymes, which are involved in the metabolism of benzodiazepines. It is unclear whether sex influences outcomes associated with intranasally administered drugs. A post hoc analysis of sex differences was conducted to evaluate the effectiveness and safety of diazepam nasal spray, which included examining changes in the number of days between seizure clusters over time (SEIzure interVAL [SEIVAL]). Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Data from a phase 3 safety study were used to determine the proportion of second doses used within 24 h (ie, a proxy for effectiveness) and SEIVAL. Adverse events were recorded. Of 163 treated patients, 89 were female, and 74 were male. Approximately 16% of both sexes self‐administered the study drug. A slightly higher proportion of seizure clusters was treated with a second dose in female (14.7%) than male (9.4%) patients. SEIVAL increased significantly and substantially over a year for all patients. The safety profile was generally similar between the sexes. These results suggest that potential sex differences in benzodiazepine pharmacokinetics do not meaningfully influence outcomes associated with diazepam nasal spray. Plain Language Summary Some drugs may have differences in absorption and metabolism between genders that could translate into differences in safety and effectiveness. This safety study looked at diazepam nasal spray for treating seizure clusters in patients at least 6 years old. It found that safety was about the same for females and males. For both groups, most clusters stopped after only 1 dose of the drug, and the time between treated clusters got longer over a year.

Introduction: Neurologic circadian influences, including sleep/wake transitions, processes (e.g., hormonal variation), and behavioral patterns (e.g., consumption of food and oral medications), may affect seizure patterns. Specific circadian patterns of seizures have been reported depending on type, onset location, and severity; however, data on patterns for patients with seizure clusters and effectiveness of rescue therapy by time of day are limited. Methods: We conducted post hoc analyses using patient diary data from the phase 3 safety study of diazepam nasal spray, which is indicated for acute treatment of seizure clusters in patients with epilepsy aged =6 years. Patients were administered age- and weight-based doses; second doses could be administered if needed to control a seizure cluster. We assessed clock timing of seizure-cluster onset along with second-dose use as a proxy for effectiveness. Treatment-emergent adverse events were recorded. Results: Seizure-cluster onset was observed to be generally highest during mornings and late evenings and lowest in the early evening and middle of the night. Second-dose use was not consistently associated with a specific time of day. The safety profile was consistent with that expected from previous studies of diazepam nasal spray. Conclusion: These results suggest that diazepam nasal spray can be effectively administered at any time of day. [ABSTRACT FROM AUTHOR]

Sex differences in drug pharmacokinetics include variations in the expression of the cytochrome P450 enzymes, which are involved in the metabolism of benzodiazepines. It is unclear whether sex influences outcomes associated with intranasally administered drugs. A post hoc analysis of sex differences was conducted to evaluate the effectiveness and safety of diazepam nasal spray, which included examining changes in the number of days between seizure clusters over time (SEIzure interVAL [SEIVAL]). Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Data from a phase 3 safety study were used to determine the proportion of second doses used within 24 h (ie, a proxy for effectiveness) and SEIVAL. Adverse events were recorded. Of 163 treated patients, 89 were female, and 74 were male. Approximately 16% of both sexes self‐administered the study drug. A slightly higher proportion of seizure clusters was treated with a second dose in female (14.7%) than male (9.4%) patients. SEIVAL increased significantly and substantially over a year for all patients. The safety profile was generally similar between the sexes. These results suggest that potential sex differences in benzodiazepine pharmacokinetics do not meaningfully influence outcomes associated with diazepam nasal spray. Plain Language Summary: Some drugs may have differences in absorption and metabolism between genders that could translate into differences in safety and effectiveness. This safety study looked at diazepam nasal spray for treating seizure clusters in patients at least 6 years old. It found that safety was about the same for females and males. For both groups, most clusters stopped after only 1 dose of the drug, and the time between treated clusters got longer over a year. [ABSTRACT FROM AUTHOR]

IntroductionNeurologic circadian influences, including sleep/wake transitions, processes (e.g., hormonal variation), and behavioral patterns (e.g., consumption of food and oral medications), may affect seizure patterns. Specific circadian patterns of seizures have been reported depending on type, onset location, and severity; however, data on patterns for patients with seizure clusters and effectiveness of rescue therapy by time of day are limited.MethodsWe conducted post hoc analyses using patient diary data from the phase 3 safety study of diazepam nasal spray, which is indicated for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Patients were administered age- and weight-based doses; second doses could be administered if needed to control a seizure cluster. We assessed clock timing of seizure-cluster onset along with second-dose use as a proxy for effectiveness. Treatment-emergent adverse events were recorded.ResultsSeizure-cluster onset was observed to be generally highest during mornings and late evenings and lowest in the early evening and middle of the night. Second-dose use was not consistently associated with a specific time of day. The safety profile was consistent with that expected from previous studies of diazepam nasal spray.ConclusionThese results suggest that diazepam nasal spray can be effectively administered at any time of day.

Epilepsy is a common neurological disorder in the United States, affecting approximately 1.2% of the population. Some people with epilepsy may experience seizure clusters, which are acute repetitive seizures that differ from the person's usual seizure pattern. Seizure clusters are unpredictable, are emotionally burdensome to patients and caregivers (including care partners), and require prompt treatment to prevent progression to serious outcomes, including status epilepticus and associated morbidity (e.g., lacerations, fractures due to falls) and mortality. Rescue medications for community use can be administered to terminate a seizure cluster, and benzodiazepines are the cornerstone of rescue treatment. Despite the effectiveness of benzodiazepines and the importance of a rapid treatment approach, as many as 80% of adult patients do not use rescue medication to treat seizure clusters. This narrative review provides an update on rescue medications used for treatment of seizure clusters, with an emphasis on clinical development and study programs for diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. Results from long-term clinical trials have shown that treatments for seizure clusters are effective. Intranasal benzodiazepines provide ease of use and patient and caregiver satisfaction in pediatric and adult patients. Adverse events attributed to acute rescue treatments have been characterized as mild to moderate, and no reports of respiratory depression have been attributed to treatment in long-term safety studies. The implementation of an acute seizure action plan to facilitate optimal use of rescue medications provides an opportunity for improved management of seizure clusters, allowing those affected to resume normal daily activities more quickly. Plain Language Summary: Some people with epilepsy who take antiseizure medications may still have seizures. These seizures might happen in clusters. Seizure clusters are emergencies that need to be treated quickly to lower the risk of status epilepticus and hospitalization. Also, these clusters can be stressful. Approved rescue medications are diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. They can all be used by family and other caregivers, and nasal sprays may be preferred in a public setting. All of these treatments can be used for adults, but each has a different age limit for children. Overall, these therapies are underused; however, all have been shown to work in stopping seizure clusters and have mild to moderate side effects. Nasal treatments offer ease of use and satisfaction for patients and caregivers (care partners). However, data for some effects and patient groups are not available for all treatments. Seizure action plans are designed to give step-by-step instructions about when and how to use rescue medication. Increased use of action plans may improve at-home treatment of seizure clusters and allow patients to perform their normal daily activities and avoid injury or hospitalizations. [ABSTRACT FROM AUTHOR]

Abstract Epilepsy is a common neurological disorder in the United States, affecting approximately 1.2% of the population. Some people with epilepsy may experience seizure clusters, which are acute repetitive seizures that differ from the person’s usual seizure pattern. Seizure clusters are unpredictable, are emotionally burdensome to patients and caregivers (including care partners), and require prompt treatment to prevent progression to serious outcomes, including status epilepticus and associated morbidity (e.g., lacerations, fractures due to falls) and mortality. Rescue medications for community use can be administered to terminate a seizure cluster, and benzodiazepines are the cornerstone of rescue treatment. Despite the effectiveness of benzodiazepines and the importance of a rapid treatment approach, as many as 80% of adult patients do not use rescue medication to treat seizure clusters. This narrative review provides an update on rescue medications used for treatment of seizure clusters, with an emphasis on clinical development and study programs for diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. Results from long-term clinical trials have shown that treatments for seizure clusters are effective. Intranasal benzodiazepines provide ease of use and patient and caregiver satisfaction in pediatric and adult patients. Adverse events attributed to acute rescue treatments have been characterized as mild to moderate, and no reports of respiratory depression have been attributed to treatment in long-term safety studies. The implementation of an acute seizure action plan to facilitate optimal use of rescue medications provides an opportunity for improved management of seizure clusters, allowing those affected to resume normal daily activities more quickly.

Objective: We assessed whether (1) women with statistical clustering of daily seizure counts (DSCs) or seizure intervals (SIs) also showed clinical clustering, defined separately by ≥2 (≥2‐SC) and ≥3 (≥3‐SC) seizures on any single day; and (2) how these classifiers might apply to catamenial epilepsy. Methods: This is a retrospective case–control analysis of data from 50 women with epilepsy (WWE). We assessed the relationships of the four classifiers to each other and to catamenial versus noncatamenial epilepsy using chi‐squared, correlation, logistic regression, and receiver operating characteristic (ROC) analyses. Results: ≥3‐SC, not ≥2‐SC, was more frequent in WWE who had statistical DSC clustering versus those who did not (21/25 [84.0%] vs. 11/25 [44.0%], p =.007). Logistic regression (p =.006) and ROC (p =.015) identified ≥3‐SC, not ≥2‐SC, as a predictor of statistical DSC clustering, but ≥4‐SC was more accurate. ≥3‐SC correlated with the average daily seizure frequencies (ADSFs) of the subjects (p =.01). ROC optimal sensitivity–specificity cut‐point for ADSF prediction of ≥3‐SC (.372) was 64.6% higher than for ≥2‐SC (.226). SI clustering was more common in WWE who had catamenial versus noncatamenial epilepsy (p =.013). Logistic regression identified statistical SI clustering as the only significant classifier (p =.043). ROC analysis offered only marginal support (p =.056), because specificity was low (42.1%). Significance: The findings lend statistical support for (1) the utility of clinical ≥3‐SC as a predictor of convulsive status epilepticus, (2) consideration of ADSFs in defining clustering, and (3) ≥4‐SC as a more accurate clinical predictor of statistical DSC clustering. Statistical SI clustering occurred more frequently in women with catamenial than noncatamenial epilepsy (90.3% vs. 57.9%, p =.013). Although sensitivity was high (90.3%, 28/31), specificity was only 42.1% (8/19). Algorithms that test patterns and periodicities of clusters are more applicable. [ABSTRACT FROM AUTHOR]

Objectives: Acute repetitive seizures (ARSs) are one of the few commonly encountered neurological emergencies in children. There is a need for an appropriate timeline-based treatment protocol, which will be shown to be safe and efficacious in a clinical study. Materials and Methods: This was a retrospective chart review to determine the efficacy of a pre-specified treatment protocol for the management of ARSs in children aged 1-18 years. The treatment protocol was specifically applied in children with a diagnosis of epilepsy and not critically ill, who met the criteria for ARSs, with the exemption of new onset of ARSs. The first tier of treatment protocol focused on intravenous lorazepam, optimization of dose of existing anti-seizure medications (ASMs), and control of triggers like acute febrile illness, while second-tier focused on adding one or two additional ASMs, commonly used in cases with seizure clusters or status epilepticus. Results: We included the first 100 consecutive patients (7.6 ± 3.2 years, 63% boys). Our treatment protocol was successful in 89 patients (58 and 31 required first-tier and second-tier treatment). The absence of pre-existing drug-resistant epilepsy and the presence of acute febrile illness as a triggering factor (P = 0.02 and 0.03) were associated with the success of the first tier of the treatment protocol. Excessive sedation (n = 29), incoordination (n = 14), transient gait instability (n = 11), and excessive irritability (n = 5) were the most common adverse effects observed during the initial 1 week. Conclusion: This pre-specified treatment protocol is safe and efficacious in controlling ARSs in cases with established epilepsy who are not critically sick. External validation from other parts of the world/centers and a more diverse epilepsy population are required before generalizing the protocol into clinical practice. [ABSTRACT FROM AUTHOR]

Acute seizure therapies given out of the hospital are important for interrupting acute repetitive and prolonged seizures and preventing hospitalization. These vary in their administration routes, indications for children and adults, pharmacologic profiles, and efficacy. We reviewed and compared the uses of current formulations available to treat acute seizures, including newly released intranasal (IN) benzodiazepines and older formulations which are widely used for interrupting seizures. [ABSTRACT FROM AUTHOR]

Adrian L Rabinowicz,1 Edward Faught,2 David F Cook,1 Enrique Carrazana1,3 1Clinical Development & Medical Affairs, Neurelis, Inc., San Diego, CA, USA; 2Emory Epilepsy Program, Emory University School of Medicine, Atlanta, GA, USA; 3John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USACorrespondence: Edward Faught, Department of Neurology, Emory University School of Medicine, 12 Executive Park Drive, NE, Atlanta, GA, 30329, USA, Tel +1 404 778-3444, Email rfaught@emory.eduPurpose: People with epilepsy may experience seizure clusters despite a stable regimen of antiseizure medications. Such clusters have the potential to last ≥ 24 hours, typically occur in the community setting, and may progress to medical emergencies, such as status epilepticus, if untreated. Thus, long-acting rescue therapy for seizure clusters is needed that can be administered by nonmedical individuals outside a hospital. Benzodiazepines are the foundation of rescue therapy for seizure clusters. The approved outpatient treatments (ie, diazepam, midazolam) have differing profiles that may affect multiple aspects of health-care utilization. The current labeling of these medications allows for a second dose if needed to control the cluster. Although no head-to-head studies directly comparing rescue treatments have been conducted, differences between studies with generally similar designs may provide context for the potential importance of second doses of rescue therapy on health-care utilization.Methods: For this analysis, large, long-term, open-label studies of approved seizure-cluster treatments designed for use by nonmedical caregivers were reviewed, and the percentage of seizure clusters for which a second dose was used or that were not controlled at 6, 12, and 24 hours was examined. Available data on hospitalizations were also collected.Results: The 3 identified studies meeting the inclusion criteria were for use of diazepam rectal gel, intranasal midazolam, and diazepam nasal spray. Across these studies, the use of a second dose ranged from < 40% at 6 hours to < 13% at 24 hours. Hospitalizations and serious treatment-emergent adverse events were reported variably across these studies.Conclusion: These results demonstrate the importance of second doses of rescue therapy for seizure clusters for optimizing health-care utilization. Need for second doses should be included as one component. In turn, when second doses are needed, they have the potential to curtail emergency department use and hospitalization and to prevent further seizure clusters.Keywords: diazepam, midazolam, nasal, rectal, acute repetitive seizures, twenty-four hours

Purpose of review: This article reviews the current evidence-based treatments for the management of acute repetitive seizures (ARS). Recent findings: Half of patients with refractory epilepsy will experience ARS, but rescue medications are underutilized. Benzodiazepines remain first-line treatment for the management of acute seizures. There are multiple approved medications, and ongoing studies investigating new routes of administration. Summary: Clinicians must recognize patients at risk of acute repetitive seizures and be aware of available options for their treatment in the outpatient setting. Additional research is needed to identify which specific treatments are best for different types of patients. [ABSTRACT FROM AUTHOR]

Patients with epilepsy (PWE) may experience seizure emergencies including acute repetitive seizures despite chronic treatment with daily antiseizure medications. Seizures may adversely impact routine daily activities and/or healthcare utilization and may impair the quality of life of patients with epilepsy and their caregivers. Seizures often occur at home, school, or work in a community setting. Appropriate treatment that is readily accessible for patients with seizure urgencies and emergencies is essential outside the hospital setting. When determining the best acute antiseizure therapy for PWE, clinicians need to consider all of the available rescue medications and their routes of administration including the safety and efficacy profiles. Benzodiazepines are a standard of care as a rescue therapy, yet there are several misconceptions about their use and safety. Reevaluating potential misconceptions and formulating best practices are necessary to maximize usage for each available option of acute therapy. We examine common beliefs associated with traditional use of acute seizure therapies to refute or support them based on the current level of evidence in the published literature.

Background: Determine the prevalence of seizure clusters (two or more seizures in six hours), use of rescue medications, and adverse outcomes associated with seizure clusters in pediatric patients with a range of epilepsy severities, and identify risk factors predictive of seizure clusters.Methods: Prospective observational two-center study, including phone call and seizure diary follow-up for 12 months in patients with epilepsy aged one month to 18 years. We classified patients into three risk groups based on seizures within the prior year: high, seizure cluster (two or more seizures within one day); intermediate, at least one seizure but no days with two or more seizures; low, no seizures.Results: One-third (32.3%; high risk, 72.4%; intermediate risk, 30.4%; low risk, 3.1%) of 297 patients had a seizure cluster during the study, including half (46.2%) of the patients with active seizures at baseline (intermediate- and high-risk groups combined). Emergency room visits or injuries were no more likely due to a seizure cluster than an isolated seizure. Rescue medications were utilized in 15.8% of patients in the high-risk group and 19.2% in the intermediate-risk group. History of status epilepticus (adjusted odds ratio [aOR], 2.13; confidence interval [CI], 1.09 to 4.16]), seizure frequency greater than four per month (aOR, 4.27; CI, 1.92 to 9.50), and high-risk group status (aOR, 6.42; CI, 2.97 to 13.87) were associated with greater odds of seizure cluster.Conclusions: Seizure clusters are common in pediatric patients with epilepsy. High seizure frequency was the strongest predictor of clusters. Rescue medications were underutilized. Future studies should evaluate the applicability and effectiveness of these medications for optimization of pediatric seizure cluster treatment and reduction of seizure-related emergency department visits, injuries, and mortality. [ABSTRACT FROM AUTHOR]

Objective: Intermittent rescue therapy may be used for seizure clusters, which are clinical emergencies that may persist ≥24 h and increase risk of status epilepticus, emergency room visits, and reduced quality of life for patients with epilepsy. Beyond effectiveness for aborting seizure clusters, no data exist on how intermittent rescue therapy may impact the long‐term natural course of seizure clusters. This novel analysis explores SEIzure interVAL (SEIVAL; time between seizure clusters) in patients from a long‐term safety study of diazepam nasal spray (Valtoco) to assess SEIVAL changes with intermittent rescue therapy across time. Methods: Patients were aged 6–65 years. Age‐ and weight‐based doses of diazepam nasal spray were administered during a 12‐month treatment period with an optional follow‐up period. SEIVAL was evaluated in patients receiving two or more doses of diazepam nasal spray using 90‐day periods. Results: Of 163 treated patients, 151 had one or more SEIVALs. One hundred twenty had SEIVALs in Period 1 and one or more other periods. An increase in SEIVAL was noted from Period 1 compared with all subsequent periods (p ≤.001). A consistent cohort (n = 76) had one or more SEIVALs in each of Periods 1–4 (360 days); mean SEIVALs increased significantly (p <.01) from 12.2 days (Period 1) to 25.7 days (Period 4). Similar SEIVAL patterns occurred when repeat doses within a seizure cluster were eliminated and irrespective of age group, treatment duration, and change to concomitant medications. In adults, Quality of Life in Epilepsy scores were maintained with increased SEIVALs. Significance: Across 12 months, increases in SEIVAL were demonstrated in patients using diazepam nasal spray for seizure cluster treatment in a phase 3 safety study. Increased time between seizure clusters may reflect a previously unrecognized beneficial effect of intermittent rescue therapy. These results generate a range of biological and behavioral hypotheses and warrant exploration of the impact of intermittent rescue therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Seizure clusters (SCs) are associated with adverse outcomes but are understudied. • This claims-based, 4-cohort study included patients with epilepsy experiencing SCs. • Patients with SCs had higher epilepsy-related healthcare resource use and costs. • Providers who specialize in treating patients with SCs could lower SC burden. Seizure clusters are underresearched and associated with adverse outcomes in patients with epilepsy. This study was a noninterventional, retrospective claims-based analysis using the Wisconsin Health Information Organization (WHIO) All-Payer Claims Database to characterize the epilepsy population in Wisconsin, with a focus on prevalence, treatment patterns, and healthcare resource utilization (HCRU) in patients with seizure clusters prior to the introduction of nasal spray rescue medications. This timeframe allows characterization of a historical baseline for future comparisons with newer treatments. Four cohorts were defined: (1) all-epilepsy (all patients with epilepsy); and subcohorts of: (2) patients receiving a monotherapy antiseizure medication (ASM); (3) patients receiving ASM polytherapy; and (4) patients treated for seizure clusters (ie, those taking rescue medications and ≥ 1 ASM). Primary outcomes were HCRU over a 12-month follow-up period, which were descriptively analyzed. Between 2017 and 2019, 16,384 patients were included in the all-epilepsy cohort; 11,688 (71.3 %) were on monotherapy, 3,849 (23.5 %) were on polytherapy, and 526 (3.2 %) were treated for seizure clusters. Twelve-month retentions to the ASM treatments were 46.7 % (7,895/16,904) in the all-epilepsy cohort, and 40.0 % (4,679/11,688) and 40.1 % (1,544/3,849) in the monotherapy and polytherapy subcohorts, respectively. Rescue medication prescriptions were obtained 1,029 times by the 526 patients in the treated seizure cluster subcohort, with infrequent refill rates (mean 1.6–1.9 times/year). A higher proportion of patients in the treated seizure cluster subcohort had epilepsy-related outpatient visits (89.7 %), other visits (71.3 %), and hospitalizations (25.3 %) than patients in the monotherapy (72.2 %, 50.2 %, 19.3 %, respectively) and polytherapy (83.3 %, 63.3 %, 22.8 %, respectively) subcohorts. Mean (standard deviation) all-cause ($114,717 [$231,667]) and epilepsy-related ($76,134 [$204,930]) costs over 12 months were higher in the treated seizure cluster subcohort than the monotherapy ($89,324 [$220,181] and $30,745 [$145,977], respectively) and polytherapy ($101,506 [$152,931] and $49,383 [$96,285], respectively) subcohorts. Patients treated for seizure clusters incurred higher all-cause and epilepsy-related costs and epilepsy-related HCRU than other subcohorts and had infrequent rescue medication refills. The findings of this analysis highlight the need for appropriate treatment for those patients with epilepsy experiencing seizure clusters. The effect of newer rescue medications to alter these findings will be explored in a follow-up study. Regardless, specialist providers with expertise in treating refractory epilepsy and seizure cluster patients may help to reduce the burden of seizure clusters. [ABSTRACT FROM AUTHOR]

Seizure clusters may initiate a chain of events that have economic as well as clinical consequences. The potential economic consequences of seizure clusters must be weighed against the cost of medication to attenuate them. This is true both for individual patients and for society. Data needed for economic analyses include the chance that a cluster will progress to an adverse outcome, such as a need for emergency care, the costs of such an outcome, the cost of a rescue medication (RM), and the effectiveness of the RM. Indirect costs, such as lost employment for patients and caregivers, must also be considered. Several types of economic analyses can be used to determine costs and benefits of a medical intervention. There are studies comparing different RMs from an economic perspective, but there is little direct information on the costs of using an RM versus allowing clusters to run their course. However, the high expense of consequences of seizure clusters makes it likely that effective RMs will make economic as well as medical sense for many patients. [ABSTRACT FROM AUTHOR]

The primary goal of treatment for seizure clusters is cessation of the cluster to avoid progression to more severe conditions, such as prolonged seizures and status epilepticus. Rescue therapies are key components of treatment plans for patients with seizure clusters. Three rescue therapies are approved in the United States for the treatment of seizure clusters: diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. This review characterizes the pharmacological function of rescue therapies for seizure clusters, as well as describing γ‐aminobutyric acid A (GABAA) receptor functions. GABAA receptors are heteropentamers, consisting primarily of α1‐6, β1‐3, γ2, and δ subunits in the central nervous system. These subunits can traffic to and from the membrane to regulate membrane potential. Benzodiazepines, such as diazepam and midazolam, are positive allosteric modulators of GABAA receptors, the activation of which leads to an increase in intracellular chloride, hyperpolarization of the cell membrane, and a reduction in excitation. GABAA receptor subunit mutations, dysregulation of trafficking, and degradation are associated with epilepsy. Although benzodiazepines are effective GABAA receptor modulators, individual formulations have unique profiles in practice. Diazepam rectal gel is an effective rescue therapy for seizure clusters; however, adults and adolescents may have social reservations regarding its administration. Intranasal delivery of midazolam or diazepam is a promising alternative to rectal administration because these formulations offer easy, socially acceptable administration and exhibit a rapid onset. Off‐label benzodiazepines, such as orally disintegrating lorazepam and intranasal use of an intravenous formulation of midazolam via nasal atomizer, are less well characterized regarding bioavailability and tolerability compared with approved agents. [ABSTRACT FROM AUTHOR]

This study aimed to develop and characterize a novel microemulsion-based intranasal diazepam for treating acute repetitive seizures (ARS). The solubility of diazepam was obtained in different solvents. An oil in water microemulsion was prepared with castor oil as oil phase, polyethylene glycol monostearate as surfactant, ethanol as cosurfactant, and water. The formulation was further evaluated for droplet size, zeta potential, pH, in vitro drug release, morphology using transmission electron microscopy (TEM), thermal property using differential scanning calorimetry (DSC), and stability and toxicity in the bovine nasal mucosa. The developed o/w microemulsion system exhibited a droplet size of 51.23 nm with a neutral zeta potential. The pH of microemulsion was close to the pH of nasal secretions. The TEM image revealed the spherical droplet shape, and the DSC thermogram showed conversion of diazepam from a crystalline form to an amorphous/molecular dispersion form. Histological evaluation of the microemulsion showed an intact bovine nasal mucosa without any signs of toxicity and was found to be stable at 25 °C for up to 3 months. To conclude, the reported microemulsion could be further explored as an alternative for treating ARS. [ABSTRACT FROM AUTHOR]

Background: To evaluate safety and tolerability of long-term treatment with diazepam nasal spray (Valtoco) for seizure clusters in patients aged six to 17 years.Methods: The study enrolled patients aged six to 65 years with frequent seizure clusters. Age- and weight-based doses of diazepam nasal spray were administered; second doses were permitted if needed. Safety assessments included treatment-emergent adverse events (TEAEs).Results: Of 163 treated patients, 45 (27.6%) were aged six to 11 years and 33 (20.2%) were aged 12 to 17 years. Mean doses per month were 2.1 in the 6 to 11 subgroup and 2.4 in the 12 to 17 subgroup. Of 1634 seizure clusters in pediatric patients, 186 (11.4%) required a second dose of diazepam nasal spray within 24 hours of the first dose. Similar proportions of TEAEs and serious TEAEs were reported in 6 to 11 (91.1%, 40.0%) and 12 to 17 subgroups (81.8%, 30.3%), respectively. No serious TEAEs were considered treatment related, and no patients discontinued because of TEAEs. Treatment-related TEAEs were more frequent in the 12 to 17 subgroup; only epistaxis and somnolence occurred in two or more patients overall. TEAE rates were similar across subgroups that received concomitant clobazam (90.0%), received prior diazepam rectal gel (90.9%), and were administered less than two versus greater than or equal to two doses per month (87.2% for both) of diazepam nasal spray. Most survey respondents (88%) were satisfied or very satisfied with treatment.Conclusions: In this long-term safety analysis in pediatric patients with seizure clusters, repeated doses of diazepam nasal spray demonstrated a safety profile consistent across subgroups. These data support the dosing guidelines for diazepam nasal spray according to age and weight for pediatric patients. [ABSTRACT FROM AUTHOR]

Although the treatment of epilepsy primarily focuses on prevention, recurrent seizures are unfortunately an ongoing reality, particularly in people with epilepsy who live with chronic refractory seizures. Rescue medications are agents which can be administered in urgent/emergent seizure episodes such as seizure clusters or prolonged seizures with the goal of terminating seizure activity, preventing morbidity, and decreasing the risk of further seizures. This review first discusses clinical opportunities for rescue medications, with particular attention focused on seizure clusters and prolonged seizures, including their epidemiology, risk factors, and associated morbidity. Current rescue medications, their indications, efficacy, and adverse effects are discussed. We then discuss rescue medications and formulations which are currently under development, concentrating on practical aspects relevant for clinical care. Rescue medications should be considered for all people with epilepsy with ongoing seizures. Recent rescue medications including intranasal formulations provide considerable advantages. New rescue medications are being developed which may expand opportunities for effective treatment. In the future, combining rescue medications with seizure detection and seizure prediction technologies should further expand opportunities for use and should reduce the morbidity of seizures and provide increased comfort, control, and quality of life for people living with epilepsy. [ABSTRACT FROM AUTHOR]

Objective: An exploratory analysis from a long‐term, phase 3, open‐label, repeat‐dose safety study of diazepam nasal spray for acute treatment of seizure clusters assessed the use of a second dose up to 24 hours after the initial dose and effectiveness in potentially reducing the number of seizures. Methods: Seizures and doses were recorded in diaries. Results: Of 175 patients enrolled, 163 received ≥1 dose of diazepam nasal spray and were included in the safety population; those patients received a total of 4390 doses for a total of 3853 seizure clusters. Less than half of these patients used a second dose a least once during the study (79 patients [48.5%]), with a total of 485 second doses for seizure clusters (12.6% of all seizure clusters). Among these 79 patients, 33 (41.8%) used only one second dose during the study (range: 1–82). The proportion of seizure clusters treated with a second dose over time was consistently low across 24 h: 0–4 h, 152 (3.9%); 4–6 h, 72 (1.9%); 6–8 h, 39 (1.0%); 8–12 h, 55 (1.4%); 12–16 h, 42 (1.1%); 16–20 h, 42 (1.1%); 20–24 h, 83 (2.2%). Rates of treatment‐emergent adverse events (TEAEs) and treatment‐related TEAEs occurring within 1 day of a second dose were low (15.2% and 5.1%, respectively). Significance: Patients with epilepsy may experience seizure clusters lasting up to 24 hours, and little is known about the effectiveness of rescue therapies for that duration. The current labeling of the US Food and Drug Administration (FDA)–approved outpatient treatments for seizure clusters (rectal diazepam, intranasal midazolam, and diazepam nasal spray) allows for a second dose, if needed, for control. These findings support the safety profile of second doses, and the low use supports the effectiveness of diazepam nasal spray across 24 hours. [ABSTRACT FROM AUTHOR]

Abstract Background Midazolam delivered by continuous rate infusion (CRI) might be effective in dogs with cluster seizures (CS) or status epilepticus (SE). Objective To describe the use and safety of midazolam CRI in dogs with CS or SE. Animals One‐hundred six client‐owned dogs presenting to a veterinary teaching hospital with CS or SE. Methods Retrospective review of medical records for dogs with CS or SE treated with a midazolam CRI. Results Seventy‐nine dogs presented with CS and 27 dogs had SE. Seizure control was achieved in 82/106 dogs (77.4%) receiving a midazolam CRI. The median dose associated with seizure control was 0.3 mg/kg/h (range, 0.1‐2.5 mg/kg/h). The median duration of CRI was 25 hours (range, 2‐96 hours). Seizures were controlled in 34/40 dogs (85%) with idiopathic epilepsy, 32/43 dogs (74%) with structural epilepsy, 12/16 dogs (75%) with unknown epilepsy, and 4/7 dogs (57%) with reactive seizures (P = .20). Seizure control was achieved in 81% of dogs with CS and 67% in dogs with SE (P = .18). Dogs with idiopathic/unknown epilepsy were more likely to survive than those with structural epilepsy (87% vs 63%, P = .009). Adverse effects were reported in 24 dogs (22.6%) and were mild in all cases. Conclusions and Clinical Importance Midazolam CRI is apparently safe and might be an effective treatment in dogs with CS or SE.

Some people with epilepsy experience acute repetitive seizures (ARS), also termed seizure clusters, which have a negative impact on patient and caregiver quality of life, emotional wellbeing, daily function, and may pose risk of injury or death. In addition, these events increase healthcare utilization in emergency departments and hospitals, which might be avoided with use of an at-home rescue medication. Intranasal formulations of benzodiazepines used as rescue medications provide a means of delivering rescue medication that is socially acceptable and more easily administered than rectal drug. This article provides a review of intranasal diazepam covering development, pharmacokinetics, dosing, safety, adverse effects, and efficacy. The authors compare it with rectal diazepam and intranasal midazolam. Intranasal rescue drugs are a valuable treatment modality for seizure clusters and prolonged seizures that are effective and well tolerated with the potential to enhance patient quality of life, reduce the incidence of seizure-related injury, and lessen the need for hospital visits. The literature does not provide evidence comparing the various rescue agents, and head-to-head comparison studies are needed. An inhaled benzodiazepine as a seizure rescue drug is currently undergoing clinical trials. [ABSTRACT FROM AUTHOR]

Seizure clusters must be treated quickly and effectively to prevent progression to prolonged seizures and status epilepticus. Rescue therapy for seizure clusters has focused on the use of benzodiazepines. Although intravenous benzodiazepine administration is the primary route in hospitals and emergency departments, seizure clusters typically occur in out‐of‐hospital settings, where a more portable product that can be easily administered by nonmedical caregivers is needed. Thus, other methods of administration have been examined, including rectal, intranasal, intramuscular, and buccal routes. Following US Food and Drug Administration (FDA) approval in 1997, rectal diazepam became the mainstay of out‐of‐hospital treatment for seizure clusters in the United States. However, social acceptability and consistent bioavailability present limitations. Intranasal formulations have potential advantages for rescue therapies, including ease of administration and faster onset of action. A midazolam nasal spray was approved by the FDA in 2019 for patients aged 12 years or older. In early 2020, the FDA approved a diazepam nasal spray for patients aged 6 years or older, which has a different formulation than the midazolam nasal product and enhances aspects of bioavailability. Benzodiazepines, including diazepam, present significant challenges in developing a suitable intranasal formulation. Diazepam nasal spray contains dodecyl maltoside (DDM) as an absorption enhancer and vitamin E to increase solubility in an easy‐to‐use portable device. In a Phase 1 study, absolute bioavailability of the diazepam nasal spray was 97% compared with intravenous diazepam. Subsequently, the nasal spray demonstrated less variability in bioavailability than rectal gel (percentage of geometric coefficient of variation of area under the curve = 42%–66% for diazepam nasal spray compared with 87%–172% for rectal gel). The diazepam nasal spray safety profile is consistent with that expected for rectal diazepam, with low rates of nasal discomfort (≤6%). To further improve the efficacy of rescue therapy, investigation of novel intranasal benzodiazepine formulations is underway. [ABSTRACT FROM AUTHOR]

Abstract Introduction Intravenous levetiracetam (IV LEV) is approved for treatment status epilepticus (SE). However, the drug’s high cost must be considered when deciding on a treatment strategy. This study aimed to compare the efficacy of brand-name and generic IV LEV for acute repetitive convulsive seizure (ARCS) or SE. Methods Forty patients aged 18 years or older who had been diagnosed with SE or ARCS were included in this double-blind study. Patients were randomly assigned at a 1:1 ratio (via computer-generated code) to receive either brand-name or generic IV LEV. The primary outcomes were seizure control and the number of seizure exacerbations during the 24 h after drug administration, while the secondary outcomes were electroencephalographic (EEG) findings, serious adverse events, and clinical outcome at hospital discharge. Results Forty patients were randomly assigned administration with either brand-name IV LEV (10 SE and 10 ARCS patients) or generic IV LEV; 7 SE and 13 ARCS patients). There was no significant difference in patients’ baseline characteristics. The seizure control rate was 75% in the brand-name IV LEV group and 65% in the generic IV LEV group (p value: 0.490). Five (25%) patients in the brand-name IV LEV group, and six (30%) patients in the generic IV LEV group developed seizure exacerbations within 24 h after drug administration (p value 0.723). There were no reports of drug-related adverse events. Two of the patients taking brand-name IV LEV and one taking the generic IV LEV died (p value > 0.999). Conclusion Treatment with the generic IV LEV had comparable outcomes with brand-name IV LEV. The generic IV LEV may be an alternative medication for the treatment of SE and ARCS to reduce treatment costs. Trial Registration TCTR20190513001. Funding Great Eastern Drug Company.

Approximately 40% of epilepsy patients will continue to experience breakthrough seizures despite stable antiepileptic drug regimens. Rescue treatments have demonstrated efficacy and safety for select seizure emergencies. Outpatient administered intranasal and rectally delivered medications are regulatory approved for acute repetitive seizures (ARS), and injectable benzodiazepines are indicated for parenteral treatment of established status epilepticus. Despite these advances, no studies have been shown to abort an ongoing seizure following patient or caregiver home administration of therapy at the first clinical sign of seizure onset. Such treatment would require rapid systemic absorption without intravenous access, and evidence of seizure cessation within minutes of administration that is superior to placebo (eg, seizure self-regulation). Rapid epileptic seizure termination (REST) treatment may apply to multiple seizure emergencies beyond ARS, including focal or generalized seizures preceded by an aura, flurries of absence or myoclonic seizures, or prolonged focal and generalized seizures at high risk of progression to status epilepticus. Novel investigational drug delivery systems have demonstrated feasibility of intraictal delivery and seizure cessation by two minutes. Ongoing randomized trials of REST treatment for diverse seizure emergencies hold the potential to decrease bouts of mental and physical incapacitation in patients with drug-resistant epilepsy.

Background: Midazolam delivered by continuous rate infusion (CRI) might be effective in dogs with cluster seizures (CS) or status epilepticus (SE). Objective: To describe the use and safety of midazolam CRI in dogs with CS or SE. Animals One‐hundred six client‐owned dogs presenting to a veterinary teaching hospital with CS or SE. Methods: Retrospective review of medical records for dogs with CS or SE treated with a midazolam CRI. Results: Seventy‐nine dogs presented with CS and 27 dogs had SE. Seizure control was achieved in 82/106 dogs (77.4%) receiving a midazolam CRI. The median dose associated with seizure control was 0.3 mg/kg/h (range, 0.1‐2.5 mg/kg/h). The median duration of CRI was 25 hours (range, 2‐96 hours). Seizures were controlled in 34/40 dogs (85%) with idiopathic epilepsy, 32/43 dogs (74%) with structural epilepsy, 12/16 dogs (75%) with unknown epilepsy, and 4/7 dogs (57%) with reactive seizures (P =.20). Seizure control was achieved in 81% of dogs with CS and 67% in dogs with SE (P =.18). Dogs with idiopathic/unknown epilepsy were more likely to survive than those with structural epilepsy (87% vs 63%, P =.009). Adverse effects were reported in 24 dogs (22.6%) and were mild in all cases. Conclusions and Clinical Importance: Midazolam CRI is apparently safe and might be an effective treatment in dogs with CS or SE. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) lactate concentrations increase after seizure activity in many human patients independent of the underlying disease process. The effect of seizure activity on CSF lactate concentration in dogs is unknown. Hypothesis/Objectives: Cerebrospinal fluid lactate concentration is unaffected by seizure activity in dogs and is more dependent on the underlying disease process causing the seizures. Animals One‐hundred eighteen client‐owned dogs with seizure disorders. Methods: Case series. Cerebrospinal fluid lactate concentration was determined using a commercially available lactate monitor. Seizure semiology, time from last seizure to CSF collection, number of seizures within the 72 hours preceding CSF collection, and clinical diagnosis were recorded. Results: Dogs with focal seizures had higher CSF lactate concentrations than did those with generalized seizures (P =.03). No differences in lactate concentrations were found among dogs with single seizures, cluster seizures or status epilepticus (P =.12), among dogs with CSF collection at different time points after the last seizure activity (P =.39) or among dogs having different numbers of seizures within the 72 hours preceding CSF collection (P =.42). A significant difference (P =.001) was found in CSF lactate concentrations among diagnostic groups, and dogs with inflammatory and neoplastic disease had higher concentrations than did dogs with idiopathic or unknown epilepsy. Conclusions and Clinical Importance: Cerebrospinal fluid lactate concentration is minimally affected by seizure activity in dogs and increased concentrations are more likely associated with the underlying disease process. [ABSTRACT FROM AUTHOR]

NRL‐1 is a novel intranasal formulation of diazepam that is being evaluated as rescue medication in patients with epilepsy who experience bouts of increased seizure activity despite stable regimens of antiepileptic drugs. This phase 1, open‐label, randomized, crossover study in healthy adult volunteers consisted of 3 single‐dose periods (5, 10, and 20 mg) followed by a 2‐dose period (2 × 10 mg) with a minimum 28‐day washout between treatments. Blood samples were taken at prespecified time points after intranasal dosing, and bioanalytic analysis of diazepam and nordiazepam was conducted using a validated liquid chromatography–tandem mass spectrometry method. Plasma pharmacokinetic parameters were summarized using descriptive statistics, and dose proportionality (peak concentration [Cmax] and area under the plasma concentration–time curve [AUC0‐∞]) was evaluated based on a power model within a 90%CI of 0.84 to 1.16. Comparisons were also conducted between single 10‐mg dose and multidose (2 × 10 mg) treatments. NRL‐1 administration resulted in rapid diazepam absorption (median time to peak concentration 1.4‐1.5 hours). Plasma concentration‐time profiles showed similar patterns of exposure that appeared to be dose dependent, with Cmax of 85.6, 133.6, and 235.3 ng/mL for the 5‐, 10‐, and 20‐mg doses, respectively, although the lower 90%CI for Cmax and AUC0‐∞ exceeded dose proportionality criteria. The coefficient of variation ranged from 59% to 67% for Cmax and 48% to 56% for AUC parameters. Dose‐normalized AUC0–∞ values were comparable between the 2 × 10‐mg and single 10‐mg doses. Treatment‐emergent adverse events were consistent with those expected for diazepam, with transient somnolence the most frequent adverse event (94.4%). These results support NRL‐1 as a potential therapy for managing seizure emergencies. [ABSTRACT FROM AUTHOR]

Objective: The study assesses the bioavailability of diazepam after intranasal administration (diazepam nasal spray) in healthy volunteers. Comparative agents were diazepam rectal gel, which served as the regulatory reference product; and oral diazepam, a product with decades of clinical use. Tolerability of diazepam nasal spray was also assessed. Methods: This was a phase 1, open‐label, randomized, single‐dose, three‐treatment, three‐period, six‐sequence crossover study in 48 healthy adult subjects that consisted of a screening period, a baseline period, and an open‐label treatment period. Interperiod intervals were at least 28 days. Results: Forty‐eight healthy volunteer subjects were enrolled, two of whom discontinued before receiving study medication. For all routes of administration, the onset of diazepam absorption was rapid, with measurable concentrations of drug present by the first sample time point. The tmax (time to reach maximum plasma concentration) was similar for diazepam nasal spray and diazepam rectal gel, both of which were slower than oral diazepam in fasted individuals. Variability (as defined by % coefficient of variation of geometric mean) in peak plasma concentration and area under the curve0‐∞ was lowest with oral diazepam, followed by diazepam nasal spray, with diazepam rectal gel showing the greatest variability. Overall, 131 treatment‐emergent adverse events (TEAEs) were considered mild (42 subjects, 91.3%), four TEAEs were considered moderate (four subjects, 8.3%), and no TEAEs were considered severe. The most commonly reported TEAE was somnolence at 56.5% (26/46) during diazepam nasal spray treatment, 89.1% (41/46) with the rectal diazepam gel treatment, and 82.6% (38/46) with oral diazepam treatment. No nasal irritation was observed for the majority of the subjects at any time point after administration, with no score higher than 2 ("minor bleeding that stops within 1 minute"). Significance: Diazepam nasal spray shows predicable pharmacokinetics and represents a potential novel therapeutic approach to control bouts of increased seizure activity (cluster seizures, acute repetitive seizures). [ABSTRACT FROM AUTHOR]

Introduction: Intravenous levetiracetam (IV LEV) is approved for treatment status epilepticus (SE). However, the drug's high cost must be considered when deciding on a treatment strategy. This study aimed to compare the efficacy of brand-name and generic IV LEV for acute repetitive convulsive seizure (ARCS) or SE. Methods: Forty patients aged 18 years or older who had been diagnosed with SE or ARCS were included in this double-blind study. Patients were randomly assigned at a 1:1 ratio (via computer-generated code) to receive either brand-name or generic IV LEV. The primary outcomes were seizure control and the number of seizure exacerbations during the 24 h after drug administration, while the secondary outcomes were electroencephalographic (EEG) findings, serious adverse events, and clinical outcome at hospital discharge. Results: Forty patients were randomly assigned administration with either brand-name IV LEV (10 SE and 10 ARCS patients) or generic IV LEV; 7 SE and 13 ARCS patients). There was no significant difference in patients' baseline characteristics. The seizure control rate was 75% in the brand-name IV LEV group and 65% in the generic IV LEV group (p value: 0.490). Five (25%) patients in the brand-name IV LEV group, and six (30%) patients in the generic IV LEV group developed seizure exacerbations within 24 h after drug administration (p value 0.723). There were no reports of drug-related adverse events. Two of the patients taking brand-name IV LEV and one taking the generic IV LEV died (p value > 0.999). Conclusion: Treatment with the generic IV LEV had comparable outcomes with brand-name IV LEV. The generic IV LEV may be an alternative medication for the treatment of SE and ARCS to reduce treatment costs. Trial Registration: TCTR20190513001. Funding: Great Eastern Drug Company. [ABSTRACT FROM AUTHOR]

• The number and type of antiseizure medications (ASMs) may impact seizure clustering in the epilepsy monitoring unit (EMU), with long-acting ASMs likely providing protection during medication withdrawal. • A higher number of pre-admissions ASMs and temporal lobe epilepsy were associated with increased seizure clustering in the EMU. • Seizure clustering in the EMU may be associated with other adverse events, such as falls and injuries. Seizure clustering, is the most frequently reported adverse event in epilepsy monitoring unit (EMU) safety studies which, can also potentiate other adverse events, such as falls, status epilepticus, and increased length of stay. The purpose of this study is to determine variables associated with increased risk of seizure clustering among patients admitted to the EMU. A retrospective review of patients admitted to the EMU over a two-year period was completed. Data collected included patient demographics, types of epilepsy, seizure frequency, anti-seizure medications (ASMs) and hospital and EMU course including incidence of seizure clustering. Two hundred seven patients were included in our study; of these, ninety patients experienced two or more seizures in a 24-hour period (24SC), and 68 patients experienced two or more seizures in a 4-hour period (4SC). Logistic regression analysis associated the absence of long-acting ASM with increased clustering within the 4SC group (p = 0.038). For every additional ASM taken by a patient at home, the odds of seizure clustering increased by 81% in the 4SC group (p = 0.009) and by 61% in the 24SC group (p = 0.022). In addition, patients with a diagnosis of temporal lobe epilepsy had some association with clustering in the 24SC group (p = 0.061). Our data showed that long-acting ASMs can be protective against seizure clustering. Furthermore, patients with temporal lobe epilepsy, and those on increased numbers of ASMs, were more likely to experience seizure clustering when undergoing medication withdrawal during an EMU evaluation. [ABSTRACT FROM AUTHOR]

Objective: To evaluate safety‐ and seizure‐related outcomes with repeated intermittent use of a novel formulation of midazolam administered as a single‐dose nasal spray (MDZ‐NS) in the outpatient treatment of patients experiencing seizure clusters (SCs). Methods: In this open‐label extension trial (ClinicalTrials.gov NCT01529034), patients aged ≥12 years and on a stable regimen of antiepileptic drugs who completed the original phase III, randomized controlled trial were enrolled. Caregivers administered MDZ‐NS 5 mg when patients experienced SCs; a second dose could be given if seizures did not terminate within 10 minutes or recurred within 10 minutes‐6 hours. Patients were monitored for treatment‐emergent adverse events (TEAEs) throughout, and the main seizure‐related outcome was treatment success, defined as seizure termination within 10 minutes and no recurrence 10 minutes‐6 hours after drug administration. Results: Of 175 patients enrolled, 161 (92.0%) received ≥1 MDZ‐NS dose, for a total of 1998 SC episodes. Median time spent by patients in the trial was 16.8 months (range = 1‐55.7 months). TEAEs were experienced by 40.4% of patients within 2 days of drug administration and 57.1% overall. TEAEs reported by most patients (within 2 days and overall) were nasal discomfort (12.4%) and somnolence (9.3%). One patient each discontinued due to treatment‐related nasal discomfort and somnolence. There were no patients with treatment‐related respiratory depression, and none with TEAEs indicative of drug abuse or dependence. Treatment success criteria were met in 55% (1108/1998) of SC episodes after administration of a single 5‐mg dose and in 80.2% (617/769) with the second dose. Treatment success was consistent over treated episode number. Significance: Repeated, intermittent, acute treatment of patients experiencing SCs with MDZ‐NS in the outpatient setting was well tolerated over an extended period, with maintenance of efficacy suggesting lack of development of tolerance. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety and efficacy of a novel formulation of midazolam administered as a single‐dose nasal spray (MDZ–NS) in the outpatient treatment of patients experiencing seizure clusters (SCs). Methods: This was a phase III, randomized, double‐blind, placebo‐controlled trial (ClinicalTrials.gov NCT01390220) with patients age ≥12 years on a stable regimen of antiepileptic drugs. Following an in‐clinic test dose phase (TDP), patients entered an outpatient comparative phase (CP) and were randomized (2:1) to receive double‐blind MDZ–NS 5 mg or placebo nasal spray, administered by caregivers when they experienced an SC. The primary efficacy end point was treatment success (seizure termination within 10 minutes and no recurrence 10 minutes to 6 hours after trial drug administration). Secondary efficacy end points were proportion of patients with seizure recurrence 10 minutes to 4 hours, and time‐to‐next seizure >10 minutes after double‐blind drug administration. Safety was monitored throughout. Results: Of 292 patients administered a test dose, 262 patients were randomized, and 201 received double‐blind treatment for an SC (n = 134 MDZ–NS, n = 67 placebo, modified intent‐to‐treat population). A significantly greater proportion of MDZ–NS‐ than placebo‐treated patients achieved treatment success (53.7% vs 34.4%; P = 0.0109). Significantly, fewer MDZ–NS‐ than placebo‐treated patients experienced seizure recurrence (38.1% vs 59.7%; P = 0.0043). Time‐to‐next seizure analysis showed early separation (within 30 minutes) between MDZ–NS and placebo that was maintained throughout the 24‐hour observation period (21% difference at 24 hours; P = 0.0124). Sixteen patients (5.5%) discontinued because of a treatment‐emergent adverse event (TEAE) during the TDP and none during the CP. During the CP, 27.6% and 22.4% of patients in the MDZ–NS and placebo groups, respectively, experienced ≥1 TEAE. Significance: MDZ–NS was superior to placebo in providing rapid, sustained seizure control when administered to patients experiencing an SC in the outpatient setting and was associated with a favorable safety profile. [ABSTRACT FROM AUTHOR]

Purpose: To summarize definitions, prevalence, risk factors, consequences, and acute management of seizure clusters using rescue medications.Methods: We searched MEDLINE for studies that assessed definitions, clinical characteristics, outcomes, and use of rescue medication for aborting seizure clusters.Results: Different clinical and statistical definitions for seizure clusters have been proposed, including: ≥3 seizures in 24 h, ≥2 seizures in 24 h, and ≥2 seizures in 6 h. Most studies of seizure clusters have been conducted in tertiary epilepsy centers, with refractory epilepsy patients. Patients with severe and poorly controlled epilepsy are more likely to experience seizure clusters. Seizure clusters can result in increased health care utilization and have negative impact on the quality of life of patients and caregivers. Use of benzodiazepine rescue medications in acute management of seizure clusters can help avoid progression to status epilepticus and reduce emergency room visits. Rescue medications are underutilized in seizure clusters. Currently, rectal diazepam gel is the only FDA approved rescue medication for seizure clusters. In addition, buccal midazolam is approved in European countries for treatment of prolonged seizures. However, various non-rectal non-IV benzodiazepines are safe and effective in treating acute seizures and clusters. Most patients and caregivers preferred non-rectal routes.Conclusion: Identifying patients that are at high risk for seizure clusters, providing them with formal action plans and educating them about use of rescue medication for seizure clusters can help ameliorate the outcomes in this group of epilepsy patients. [ABSTRACT FROM AUTHOR]

Abstract Objective The purpose of this prospective observational study was to describe the prevalence and adverse outcomes associated with seizure clusters (defined as ≥ 2 seizures in a 6-hour period) in a large sample of adult patients with a range of epilepsy severities and to identify clinical characteristics predictive of clustering. Methods Patients maintained a seizure diary and were contacted monthly to verify compliance and data accuracy. Logistic regression models were utilized to test associations between individual patient demographic/clinical characteristics and seizure clustering. Fisher's exact test was utilized to test associations between rescue medication use and adverse seizure-related outcomes. Results A total of 300 patients were followed prospectively for one year; 247 patients qualified for final analysis. Six-hour seizure clusters occurred in 45.8% of patients with active epilepsy at enrollment, including 62.7% of those with prior day-clusters and 30.0% of those without prior day-clusters. The odds of clustering were markedly greater among patients who reported a higher seizure frequency (> 4 seizures per year vs. 1–4 seizures per year) (adjusted odds ratio (OR): 8.9; 95% confidence interval (CI): 3.2–24.6; p < 0.0001) and among patients with prior day-clusters (adjusted OR: 11.0; 95% CI: 1.2–104.2; p = 0.036). Rescue medication use was associated with significantly fewer injuries and emergency department visits, but rescue medication was underutilized. Conclusions Seizure clusters are common, occurring in nearly half of adult patients with active epilepsy followed prospectively over one year, and are more frequent in those with higher seizure frequencies and prior day-clusters. Although underutilized, rescue medication was associated with fewer injuries and emergency department visit. Highlights • Seizure clustering is a clinical phenomenon that is underrepresented in the literature relative to its prevalence. • Seizure clustering has the potential to seriously impact the health and well-being of adult patients with epilepsy. • Seizure clusters occurred in nearly half of adult patients with active epilepsy followed prospectively over one year. • The odds of clustering were greater in patients who reported higher seizure frequency and in those with prior day-clusters. [ABSTRACT FROM AUTHOR]

Summary: A subgroup of patients with drug‐resistant epilepsy have seizure clusters, which are a part of the continuum of seizure emergencies that includes prolonged episodes and status epilepticus. When the patient or caregiver can identify the beginning of a cluster, the condition is amenable to certain treatments, an approach known as rescue therapy. Intravenous drug administration offers the fastest onset of action, but this route is usually not an option because most seizure clusters occur outside of a medical facility. Alternate routes of administration have been used or are proposed including rectal, buccal, intrapulmonary, subcutaneous, intramuscular, and intranasal. The objective of this narrative review is to describe the (1) anatomical, physiologic, and drug physicochemical properties that need to be considered when developing therapies for seizure emergencies and (2) products currently in development. New therapies must consider parameters of Fick's law such as absorptive surface area, blood flow, membrane thickness, and lipid solubility, because these factors affect both rate and extend of absorption. For example, the lung has a 50 000‐fold greater absorptive surface area than that associated with a subcutaneous injection. Lipid solubility is a physicochemical property that influences the absorption rate of small molecule drugs. Among drugs currently used or under development for rescue therapy, allopregnanolone has the greatest lipid solubility at physiologic pH, followed by propofol, midazolam, diazepam, lorazepam, alprazolam, and brivaracetam. However, greater lipid solubility correlates with lower water solubility, complicating formulation of rescue therapies. One approach to overcoming poor aqueous solubility involves the use of a water‐soluble prodrug coadministered with a converting enzyme, which is being explored for the intranasal delivery of diazepam. With advances in seizure prediction technology and the development of drug delivery systems that provide rapid onset of effect, rescue therapies may prevent the occurrence of seizures, thus greatly improving the management of epilepsy. [ABSTRACT FROM AUTHOR]

Benzodiazepines such as diazepam, lorazepam and midazolam remained the mainstay of treatment for acute repetitive seizures (ARS). The immediate care for ARS should often begin at home by a caregiver. This prevents the progression of ARS to prolonged seizures or status epilepticus. For a long time and despite social objections rectal diazepam gel remained only FDA-approved rescue medication. Intranasal administration of benzodiazepines is considered attractive and safe compared with rectal, buccal and sublingual routes. Intranasal delivery offers numerous advantages such as large absorptive surface area, bypass the first-pass metabolism and good patient acceptance as it is needle free and painless. Recent clinical studies have demonstrated that diazepam nasal spray (NRL-1; Valtoco®, Neurelis Inc.,San Diego, CA, USA) showed less pharmacokinetic variability and reliable bioavailability compared with the diazepam rectal gel. Diazepam nasal spray could be considered as a suitable alternative for treating seizure emergencies outside the hospital. This review summarizes the treatment options for ARS and findings from clinical studies involving intranasal diazepam for treating seizure emergencies.

• We evaluated the effectiveness of sublingual lorazepam when administered to treat acute repetitive or prolonged seizures in adults. • Administration of lorazepam interrupted acute seizure activity for 67% of patients. • No patients had sedation complications with home doses of 0.5 to 2 mg. • Patients reported high satisfaction with the treatment of sublingual lorazepam. Limited acute home treatments are available for patients with prolonged (>5 minutes) or repetitive (≥2 in 24 hours) seizures. While this early seizure treatment may reduce the need for emergency care, intermittent intranasal benzodiazepine formulations are expensive and rectal diazepam administration is often socially unacceptable. We determined whether caregivers could use sublingual lorazepam oral concentrate solution effectively as acute treatment for adults with prolonged and repetitive seizures. Patients prescribed sublingual lorazepam solution at the Johns Hopkins Epilepsy Center for acute seizure treatment during a 5-year period (2012–2017) were screened. We determined clinical history of seizure patterns and number of antiseizure medications (ASMs) through patient and caregiver surveys, and we verified this history in patients' medical records and charts. During a 2-year span (2017–2018), patients and caregivers were surveyed on responses to their most recent use of sublingual lorazepam solution, including seizure cessation (prolonged seizure stopping <5 minutes or ≤1 repetitive seizure), presence of sedation and adverse events within 24 hours of administration, and whether refrigeration limited use. In total, 52 patients used sublingual lorazepam for treatment of acute seizures during the study period (median dose 1 mg, range 0.5 to 2 mg). Of them, 48 patients participated in treatment survey interviews. Family caregivers usually administered lorazepam (88%); 3 self-administered. Patients were surveyed on responses to their most recent use of sublingual lorazepam treatment: 66% (23/35) of patients with repetitive seizures reported no further seizure activity after administering treatment; 70% (7/10) with prolonged seizures reported seizure activity ceased within 5 minutes of treatment. Three patients treated auras and had no seizures. There were no serious adverse events during most recent use: 31% of patients developed moderate/severe sedation. Of note, 98% refrigerated lorazepam, often with coolers; 44%, however, said this limited treatment access. There was high treatment satisfaction; 79% reported that having the emergency treatment available made them feel safer. This patient survey and retrospective chart review demonstrates that home treatment with sublingual lorazepam solution may be effective for interrupting prolonged and repetitive seizures. No patients had sedation complications with home doses of 0.5 to 2 mg, and patients report high satisfaction with the treatment. [ABSTRACT FROM AUTHOR]

Patients with epilepsy (PWE) may experience seizure emergencies including acute repetitive seizures despite chronic treatment with daily antiseizure medications. Seizures may adversely impact routine daily activities and/or healthcare utilization and may impair the quality of life of patients with epilepsy and their caregivers. Seizures often occur at home, school, or work in a community setting. Appropriate treatment that is readily accessible for patients with seizure urgencies and emergencies is essential outside the hospital setting. When determining the best acute antiseizure therapy for PWE, clinicians need to consider all of the available rescue medications and their routes of administration including the safety and efficacy profiles. Benzodiazepines are a standard of care as a rescue therapy, yet there are several misconceptions about their use and safety. Reevaluating potential misconceptions and formulating best practices are necessary to maximize usage for each available option of acute therapy. We examine common beliefs associated with traditional use of acute seizure therapies to refute or support them based on the current level of evidence in the published literature., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Summary: Acute repetitive seizures (ARS) pose a risk of hospital admission with status epilepticus and a mortality threat, which underscores the need for the early prediction of a clinical course. Unfortunately, little attention has been given to ARS in this context, even though we possess the appropriate predictive tools for the stages of status epilepticus. Therefore, the main aim of this study was to assess the prognostic value of the Status Epilepticus Severity Score (STESS) in the population of patients with ARS. The study included a population of 200 patients. Almost half of the patients had achieved seizure cessations after diazepam administration, whereas 19.5% progressed to status epilepticus despite antiepileptic drug treatment. Mortality reached 10.5% of the total population. The receiver operating characteristic (ROC) curve for prediction of death by the STESS had an area under the curve (AUC) of 0.901, with an optimal cutoff point for discrimination ≥2 (sensitivity 0.95, specificity 0.71, and Youden index 0.66). Hosmer‐Lemeshow indicated good calibration of the STESS (chi‐square goodness‐of‐fit test = 3.24; P = .919). The study shows excellent effectiveness of the STESS in the prognosis of the clinical course in patients with ARS. STESS may be a valuable tool for the proper planning of diagnostic and therapeutic activities in this population. [ABSTRACT FROM AUTHOR]

Purpose The aim of this review was to systematically examine safety and efficacy outcomes, as well as patient/caregiver satisfaction, from clinical studies in pediatric and adult patients treated with benzodiazepines (BZDs) through various administration routes in response to seizure emergencies. Methods A literature search was conducted to identify articles describing the use of various routes of administration (RoAs) of BZDs for the treatment of seizure emergencies through April 21, 2015, using Embase™ and PubMed®. Eligible studies included (a) randomized controlled trials or (b) controlled nonrandomized clinical trials, either retrospective or prospective. Outcome assessments reviewed were 1) time to administration, 2) time to seizure termination, 3) rate of treatment failure, 4) prevention of seizure recurrence, 5) patient and caregiver treatment satisfaction, 6) adverse events related to BDZ treatment or RoA, and 7) respiratory adverse events. Results Seventy-five studies evaluated safety and efficacy using individual or comparator BDZs of various RoAs for treating seizure emergencies in all-aged patients with epilepsy. Buccal, intranasal (IN), or intramuscular (IM) BZDs were often more rapidly administered compared with rectal and intravenous (IV) formulations. Time to seizure termination, seizure recurrence rates, and adverse events were generally similar among RoAs, whereas nonrectal RoAs resulted in greater patient and caregiver satisfaction compared with rectal RoA. Significance Results of this systematic literature review suggest that nonrectal and non-IV BZD formulations provide equal or improved efficacy and safety outcomes compared with rectal and IV formulations for the treatment of seizure emergencies. [ABSTRACT FROM AUTHOR]

Epilepsy is widely prevalent globally and has emerged as a well-studied neurological condition in the recent past. Seizure clusters, a type of seizures, and several aspects pertaining to the etiopathogenesis and management of clusters are yet to be elucidated. This review is an attempt to recapitulate the current understanding of seizure clusters based on the research that has been performed on seizure clusters. This article will provide a comprehensive review of various aspects of clusters, and discusses definitions, prevalence, risk factors, impact on quality of life, approved treatment modalities, and recent advances in management. [ABSTRACT FROM AUTHOR]