Exploring proposed recommendations for immediate‐use seizure medication: Treating both cluster and prolonged seizures with diazepam nasal spray

Abstract

The Seizure Termination Project developed expert consensus recommendations for outpatient management of seizure clusters and prolonged seizures to prevent progression to a higher‐level emergency. The consensus recommendations described therapeutic scenarios for seizure clusters (acute cluster treatment [ACT]) to prevent further seizures in a cluster and treatment to stop ongoing seizures that were expected to be prolonged (rapid and early seizure termination [REST]). Here, we review ACT and REST as categories and explore their practical application by examining patient‐level data for diazepam nasal spray. ACT and REST criteria were examined using data from the long‐term safety study that evaluated diazepam nasal spray for seizure clusters. To explore the effectiveness and duration of treatment for ACT, the proportion of seizure clusters for which second doses were administered within 24 h was used as a proxy. REST was investigated using the time from administration to seizure cluster termination; timing for the termination of prolonged seizures (5–15 min for the purposes of this analysis) in clusters also was examined. In the long‐term safety study of diazepam nasal spray, a single dose demonstrated effectiveness at terminating a substantial majority of seizure clusters (3368/3853 [87.4%]) across 24 h, demonstrating its use as ACT. The majority of seizure clusters (2169/3225 [67.3%]) were recognized and treated quickly, within 5 min from onset, demonstrating its utility as REST. Notably, effectiveness was maintained in seizures treated after they had become prolonged. These findings from the large dataset of the long‐term safety study of diazepam nasal spray demonstrate that it is of benefit in immediate use for both termination of an acute seizure and prolonged seizures within seizure clusters, thus supporting the recent expert consensus recommendations. Early use of a single rescue treatment can meet the need for ACT and REST, simplifying patient care.

Plain Language Summary

An expert group defined 2 groups of seizure medicines for patients and caregivers to use. “ACT” medicines are for acute cluster treatment to prevent more seizures in a cluster. “REST” medicines for rapid and early seizure treatment stop prolonged seizures. Diazepam nasal spray for seizure clusters was looked at to see if it could fit in both categories. Study data showed that for most seizure clusters only 1 dose of diazepam nasal spray was used over 24 h (fitting ACT), and seizures were treated and ended quickly (fitting REST). One medicine for REST and ACT may make treatment simpler.

Key points.

• Acute cluster treatment (ACT) was recommended by an expert consensus group to prevent further seizures in a cluster.

• Rapid and early seizure treatment (REST) medications were recommended to stop ongoing seizures that were expected to be prolonged.

• Analyses of data from the long‐term safety study of diazepam nasal spray for seizure clusters demonstrate its utility for ACT and REST.

• Having a single medication to address both ACT and REST may help to simplify the treatment of seizure events in the acute context.

1. INTRODUCTION

Even with appropriate daily antiseizure medications, some people with epilepsy have acute seizure episodes, such as seizure clusters, which are described in medication labeling as intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient's usual seizure pattern ¹ , ² , ³ ; a consensus definition of seizure clusters is lacking. ⁴ Untreated seizure clusters are associated with an increased risk of emergency room use and progression to status epilepticus. ⁵ Indeed, seizure clusters that progress beyond 5 min (generalized convulsive seizures) or 10 min (focal seizures with impaired consciousness) without recovery of full consciousness between seizures within the cluster represent status epilepticus, ⁶ and seizures continuing, for example, 5–15 min from onset, represent prolonged seizures. ⁷ , ⁸ In turn, prolonged seizures are potential components of some patients' seizure cluster patterns. Benzodiazepine immediate‐use seizure medications (ISMs, also known as rescue medication) are used to treat seizure clusters, and prompt treatment has been shown to be more effective than delayed treatment. ⁹ , ¹⁰ Key attributes of an ideal ISM include a quick, easy‐to‐use mode of administration, efficacy at small doses, early onset and appropriate duration of action, and a good safety profile. ⁹

While for status epilepticus there is an accepted definition and are guidelines for treatment, ¹¹ the same cannot be said for either seizure clusters or for prolonged seizures. ⁴ , ¹² To help address this gap, the Seizure Termination Project developed expert consensus recommendations for outpatient management of seizure clusters and prolonged seizures to prevent progression to a higher‐level emergency. ¹² Their consensus definition of seizure clusters was “an abnormal increase in seizure frequency compared with the individual patient's usual seizure pattern.” Prolonged focal seizures were defined as ongoing seizures of >5 min, prolonged generalized absence seizures were defined as ongoing seizures of >2 min, and prolonged bilateral tonic–clonic seizures were defined as ongoing convulsive seizures of >2 min. The expert working group also identified an unmet need for medications with a rapid onset of action that could be administered quickly to terminate seizures. ¹²

The consensus recommendations described therapeutic scenarios for seizure clusters (acute cluster treatment [ACT]) to prevent further seizures in a cluster, which was differentiated from treatment to stop ongoing seizures that were expected to be prolonged (rapid and early seizure termination [REST]) (Table 1). ¹² ACT therapy was recommended to be administered to patients with seizure clusters when the pattern of onset is recognized. ¹² Prompt treatment is important for ACT and REST, as shorter duration of seizure activity is associated with increased response to benzodiazepines. ¹³ Although treatment of prolonged seizures or seizure clusters may not be new concepts, the emphasis on their importance and the value of early treatment may not be as well recognized.

TABLE 1.

Key consensus statements. ¹²

	ACT	ACT and REST	REST
Definition	Seizure clusters Abnormal increases in seizure frequency		Prolonged seizures Focal: duration >5 min Generalized absence/bilateral tonic–clonic: duration >2 min
Goal	Prevent the next or further seizures	Prevent status epilepticus Prevent progression to more serious seizure types Lower risk of hospitalization Minimize postictal time to return to normal function Reduce need for emergency services Reduce burden on caregiver Potentially: Reduce risk of cumulative neuronal damage	Terminate ongoing seizure activity (ideally in <2 min)
Patients	History of seizure clusters		History of prolonged seizures
Documentation		Seizure action plan
Administer	Potentially at onset of 1st seizure in cluster	When onset pattern recognized	Seizure is abnormally long As early as possible in patients with history and recognizable pattern: When possible for bilateral tonic–clonic seizure, >2 min of convulsive activity in patients without a history of prolonged seizures

Abbreviations: ACT, acute cluster treatment; REST, rapid and early seizure termination.

Seizure medications could potentially be defined using these new ACT and REST categories. Future therapies or studies may identify whether some agents are appropriate for both categories ¹² ; use of a single medication might have a role in helping simplify care for some patients (Figure 1). Here, we review the recommended ACT and REST categories and take a step further to explore the practical application of ACT and REST by examining published post hoc data, supplemented by new patient‐level analyses in a clinical dataset from a long‐term, open‐label safety study of diazepam nasal spray.

FIGURE 1.

Potential role of an immediate‐use seizure medication. ACT, acute cluster treatment; ISM, immediate‐use seizure medication; REST, rapid and early seizure termination.

2. AN EXISTING DATASET SUITABLE TO TEST REST AND ACT CRITERIA

ACT and REST criteria were examined separately using the dataset of all treated seizures from the total population of the long‐term safety study that evaluated diazepam nasal spray for seizure clusters. ¹⁴ ACT criteria were analyzed based on the initial treatment for a seizure cluster. For REST criteria, only data for seizures that were prolonged within seizure clusters were used. Contexts for which the expert working group recommended either an ACT or REST medication are noted where relevant. Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥2 years, ¹ which would fit under the ACT criteria.

In the long‐term safety study (mean drug exposure, nearly 1.5 years), 163 patients aged 6–65 years (median age, 23.1 years; 54.6% female) were administered diazepam nasal spray (total doses, 4390) to treat 3853 seizure clusters. ¹⁴ Seizure clusters were defined individually based on each patient's seizure pattern, and enrollment criteria included investigator opinion that benzodiazepine might be needed an average of at least once every 2 months. Patients were required to have a diagnosis of focal or generalized epilepsy with motor seizures or seizures with clear alteration of awareness and occurrence of seizures despite stable treatment with antiseizure medication. Although epilepsy and seizure type were not systematically recorded for all patients in this safety study, inclusion criteria were broad and the patient population included patients with developmental and epileptic encephalopathies (64 patients identified) and focal epilepsies (60 patients identified). ¹⁵ , ¹⁶ Seizure start, stop, and drug administration times were recorded in a patient diary. In a post hoc analysis, the number of administrations used to treat a cluster within 24 h was examined to determine whether a single dose was effective in preventing further seizures in a cluster. ¹⁴ Medical and seizure history were collected and, when sufficient data were available, these were used to assess seizure type post hoc. ¹⁵

2.1. ACT criteria

To explore the effectiveness and duration of treatment for ACT, the proportion of seizure clusters for which second doses were administered within 24 h was used as a proxy per published results of the long‐term safety study. ¹⁴ Additionally, second dose use was measured based on the time from seizure onset to use of diazepam nasal spray, using administration cutoffs of 0–1, 1–2, 2–3, 3–4, 4–5, 0–2, and 0–5 min, determined from study seizure diary entries (data on file), to assess the effect of rapid administration. As this analysis required seizure start data, it differed from the overall analysis of all second doses, because it was necessary to remove records with invalid dates and missing timing values, seizure start/stop before start, duration longer than 24 h, and multiple records with the same dose date. A similar time‐to‐dose analysis was performed to assess second doses for prolonged seizures within a cluster; prolonged seizures were defined as those for which treatment was administered 5–15 min after the seizure onset. ⁸ Quality of life results for patients with seizure clusters treated with diazepam nasal spray, measured as mean change from baseline to Day 365, were analyzed for the overall and subscale scores of the Quality of Life in Epilepsy (QOLIE)‐31‐P have been published. ¹⁷ The QOLIE‐31‐P was completed by adults aged ≥18 years (n = 72) without caregiver assistance at 5 study visits up to 1 year (days 0, 30, 150, 270, and 365). ¹⁷ Of the 7 subscales of the QOLIE‐31‐P instrument, 2 were hypothesized by study investigators to be the most affected by intermittent ISMs: Seizure Worry, which assesses concern about seizure unpredictability and associated risk, and Social Functioning, which measures how much bother the patient experiences doing daily activities. ¹⁷

2.2. REST criteria

REST was investigated using time from administration to seizure termination (in groupings of administration 0–5, 5–15, and >15 min after seizure onset), ¹⁰ including timing for termination of prolonged seizures (5–15 min for the purposes of this analysis) in clusters, as well as using minute‐by‐minute data (data on file). ⁸ , ¹⁰ To further gauge the benefit of prompt REST treatment from patients' perspectives, mean change in QOLIE‐31‐P ¹⁷ was assessed by timing of administration 0–5, 5–15, and >15 min after seizure onset determined from seizure diary entries (data on file). Finally, in a subset of patients and caregivers responding to an exit survey for the study, time categories for patients to return to their usual selves and for care partners to return to their daily activities after their most recent seizure cluster were explored. ¹⁸

3. EVALUATION OF ACT CRITERIA USING DIAZEPAM NASAL SPRAY DATA

The expert working group recommended that an ACT therapy to “prevent the next or further seizures in a cluster” should be offered to all patients with a history of seizure clusters, and an ACT or REST therapy should be offered to patients who have experienced absence or myoclonic seizures progressing to generalized tonic–clonic seizures. ¹² Other goals of ACT therapies include reduction in neurologic risks and patient and caregiver burden. ¹² Additionally, ACT and/or REST therapies should be offered with caution to patients at high risk of severe adverse events, patients at high risk of medication abuse or who have suspected drug addiction, and patients taking opioid medication. The expert working group felt that ACT and/or REST therapy might be offered to at least some patients using chronic benzodiazepine medication. The group recommended that an ACT or REST therapy be administered for patients with seizure clusters as soon as the seizure cluster is recognized and that the clinician, patient, and caregiver collaborate on a seizure action plan. ¹²

In the long‐term safety study of diazepam nasal spray, a single dose was used to treat a substantial majority of seizure clusters (3368/3853 [87.4%]), suggesting effectiveness for seizure cluster control across 24 h. ¹⁴ Second doses were administered within 24 h of the first dose for 12.6% (485/3853) of seizure clusters. Results were consistent across subgroups with higher monthly usage of diazepam nasal spray, those taking concomitant benzodiazepines, and pediatric patients. No clinically relevant difference was seen in second dose usage in analyses of patients with high monthly usage of 2–5 doses (9.7%) compared with patients in the overall safety set (1–10 doses). ¹⁴ Among pediatric patients aged 6–17 years, 11.4% (186/1634) of seizure clusters were treated with second doses. ¹⁹ Second doses were given for 3.9% (152/3853) of seizure clusters within 4 h of the first dose, 6.8% (263/3853) of seizure clusters within 8 h, and 8.3% (318/3853) of seizure clusters within 12 h. ²⁰ Of all second doses (n = 485), 9.1% (n = 44) were given 0–10 min after the initial dose. ²¹ Less than half of the patients (48.5%; n = 79) ever received a second dose during the study, and 41.8% of those patients used a second dose only once over the duration of the full study. ²⁰

Effectiveness was evaluated for administrations within the first 5 minutes based on a specific number of minutes to treatment overall and by age group, type of epilepsy, and level of use (>20 treated clusters during the study) (Figure 2) (data on file). When the first dose administration occurred 0 to <2 min after onset (n = 1277 occurrences), second doses were used for 7.1% of seizure clusters. In comparison, when the first dose was administered 0 to <5 min after onset (n = 1973 occurrences), second doses were used for 6.0% of seizure clusters. In a similar analysis examining second doses in prolonged seizures, defined in the analysis as those treated 5–15 min after onset, 9.3% (63/678) were treated with a second dose; thus, 90.7% of doses were effective. Sensitivity analyses by age, epilepsy type, and high seizure frequency showed similar trends.

FIGURE 2.

Minute‐by‐minute median proportion of seizure clusters for which second doses were administered when diazepam nasal spray is administered <5 min after onset.

Regarding patient quality of life in association with the ACT criteria, the QOLIE‐31‐P instrument was completed by adult patients with seizure clusters treated with diazepam nasal spray in the long‐term safety study (n = 72 in the overall analysis group). ¹⁷ Across the 12‐month treatment period, scores were generally stable or increased over time. Clinically important improvement was seen in mean total QOLIE‐31‐P scores from day 0 to day 365. The 2 subscales hypothesized to be the most affected by immediate‐use seizure medication, Seizure Worry and Social Functioning, demonstrated the greatest numerical increase from day 0 to day 365. The Seizure Worry mean score increased 8.7 points (from 46.3 to 55.0); the increase in Social Functioning mean score was 8.1 points (from 52.9 to 61.0). ¹⁷

4. EVALUATION OF REST CRITERIA USING DIAZEPAM NASAL SPRAY DATA

REST is presented by the expert working group as “a new management paradigm that encompasses the acute treatment of ongoing seizures,” with this type of therapy having the ability to terminate an ongoing seizure. ¹² Per that group, an ideal REST therapy would act within 2 min of administration to terminate seizure activity, with the primary goal of a REST therapy being to terminate an ongoing seizure in the shortest time possible. ¹²

The expert working group recommended that REST therapy be offered to all patients with a history of prolonged seizure, status epilepticus, or certain progressive seizures. ¹² Additionally, they recommended that patients with a recognizable pattern of prolonged seizures and those with abnormally prolonged seizures based on the patient's seizure pattern, as well as those with a history of prolonged bilateral tonic–clonic seizures, should administer a REST therapy within 2 min if possible, and ideally as early as feasible. ¹²

Because some seizure clusters also may meet the definition of prolonged seizures, patient data from the long‐term safety study of diazepam nasal spray was examined post hoc to determine whether early administration after the onset of a seizure was rapidly effective in terminating seizures lasting ≥5 min. ¹⁰ In the analysis set of 3225 seizure cluster observations from patient diaries, median time to administration was 2 min, and median time from administration to seizure termination was 3 min. The majority of seizure clusters (2169/3225 [67.3%]) were recognized and treated quickly, within 5 min from onset. Among these patients, median time to administration was 1 min and median time to seizure termination was 2 min, with most observations terminating in <5 min (Figure 3). For prolonged seizures within a cluster when diazepam nasal spray was administered in 5–15 min from onset (n = 727 occurrences), median time to administration of diazepam nasal spray was 6 min, and median time to termination was 7 min. ¹⁰ In comparison, when diazepam nasal spray was administered ≥5 min after onset (1056/3225 [32.7%]), median time to administration was 10 min, and median time to seizure termination was 10 min. ¹⁰ Thus, longer time to administration was associated with longer time to cessation of seizure clusters or prolonged seizures within a cluster.

FIGURE 3.

Diazepam nasal spray as REST therapy. REST, rapid and early seizure termination.

A sensitivity analysis removed observations with a total seizure duration of 0–2 min in seizures treated within 5 min (n = 1440 occurrences), which was designed to reduce confounding from seizures that would have spontaneously resolved, had similar results to the main <5‐min analysis: median time to administration was 1 min, and median time to seizure termination was 4 min. ¹⁰ When treatment within 0–2 min of seizure onset was analyzed (n = 1413 occurrences), median time to administration was 0 min, and median time to seizure termination was 2 min. Additionally, an analysis assessing minute‐by‐minute time to administration and time to seizure termination in the first 5 min added detailed data for early treatment, showing earlier seizure termination with earlier administration (Figure 4) (data on file).

FIGURE 4.

Minute‐by‐minute median time to administration and seizure termination when diazepam nasal spray is administered <5 min after onset.

4.1. Other important endpoints for REST

Postictal recovery, caregiver burden, and neuronal damage were not directly captured in the diazepam nasal spray study; however, a separate patient‐reported outcome, quality of life, was measured. In an assessment of the QOLIE‐31‐P instrument in adults, ¹⁷ mean change from baseline to 365 days was examined as important endpoints for patients who might be affected by prompt treatment (data on file; Figure S1). For the Overall Score, there was an increased (directionally improved) mean change from baseline for the 0–5 min (3.68 [n = 32]) and 5–15 min (3.18 [n = 12]) time‐to‐administration groups and a decreased mean change from baseline for the >15 min group (−4.91 [n = 7]). For the Seizure Worry subscale, there was an increased mean change from baseline for both the 0–5 min (0.75) and 5–15 min (0.17) time‐to‐administration groups and a decreased mean change from baseline for the >15 min group (−0.75). For the Social Functioning subscale, the greatest increased (directionally improved) change from baseline was in the 0–5 min group (1.82), followed by the 5–15 min (0.10) and >15 min (0.06) groups. Additionally, for the Cognitive Functioning subscale, there were increased mean changes from baseline for the 0–5 min (1.39) and 5–15 min (0.69) groups and a larger decrease for the >15 min group (−3.20).

In the exit survey, the majority of patients (38/64 [59.4%]) reported returning to their usual selves within an hour ¹⁸ ; over the time‐to‐administration groups (0–5 min [n = 41], 5–15 min [n = 14], and ≥15 min [n = 7], not available [n = 2]), the median timing was 30–60 min (data on file). Of the patients who reported self‐administration of diazepam nasal spray (n = 27), more than half (14/27 [51.9%]) reported returning to baseline within 30 min. ²² For care partners, 59.5% (47/79) reported returning to daily activities within an hour ¹⁸ ; the average timing across all 3 groups was 1–2 h. No clear patterns were seen in these data.

5. SAFETY ENDPOINTS FOR ACT AND REST

The ACT and REST consensus also lists reduced risk of status epilepticus and use of emergency services and hospitalization as treatment goals. ¹² The safety profile of diazepam nasal spray was shown to be consistent with that of diazepam rectal gel. ¹⁴ Treatment‐emergent adverse events (TEAEs) were reported in 82.2% of patients, serious TEAEs in 30.7% of patients, and treatment‐related TEAEs in 18.4%. The most common TEAEs (occurring in >10% of patients, irrespective of relation to treatment) in this long‐term study were seizure (19.0%), nasopharyngitis (12.3%), upper respiratory tract infection (12.3%), and pyrexia (10.4%). There were no serious treatment‐related TEAEs, and the 1 death was not considered treatment related. No cases of respiratory depression were reported. Somnolence was reported for 11 patients, with 3 considered treatment related. Nasal irritation was mostly mild and transient. ¹⁴ Status epilepticus was reported in 7 patients (4.3%), and hospitalization for any reason occurred in 44 patients (27.0%). ¹⁴ , ²³

6. ACT AND REST IN THE CONTEXT OF IMMEDIATE‐USE SEIZURE MEDICATIONS

In a review comparing data from the 3 long‐term studies of US Food and Drug Administration‐approved ISMs (rectal diazepam, midazolam nasal spray, and diazepam nasal spray), all 3 were shown to have at least 61% effectiveness of first doses in preventing further seizures in the time defined in their respective studies (diazepam rectal gel, 77.0% in 12 h; midazolam nasal spray, 61.5% in 6 h; and diazepam nasal spray 94.2% in 6 h, 91.7% in 12 h, and 87.4% in 24 h). ²³ A survey of safety and efficacy of available therapies is beyond the scope of this review, but some additional data on ACT and REST endpoints for seizure clusters and prolonged seizures have been published elsewhere. ⁹ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹

As shown here, rapid antiseizure response to diazepam nasal spray has been demonstrated in post hoc analyses of data from the long‐term safety study. Previous studies of the onset of action for diazepam rectal and oral formulations have noted an antiseizure response (i.e., reduction in spike counts) that occurred prior to achieving maximum plasma concentrations of diazepam. ³⁰ , ³¹ Time to a therapeutic effect may precede time to maximum concentration (T _max), with changes in electroencephalographic activity occurring within minutes of dosing for some formulations. ³⁰ , ³¹ As such, time to effectiveness may not be directly proportional to T _max but rather associated with reaching the therapeutic threshold, suggesting that time to administration and time to seizure termination may be independent of pharmacokinetic parameters. ³⁰ , ³² , ³³ Onset of efficacy has been demonstrated to occur rapidly with diazepam nasal spray, within minutes after administration (i.e., median of 3 min from administration to seizure termination) in the long‐term safety study, ¹⁰ well before the T _max of 1.5 h. ¹ In a preclinical study, diazepam was shown to attain minimal effectiveness at steady‐state plasma concentrations of approximately 70 ng/mL, with effects observable at concentrations as low as 30 ng/mL. ³³ In a study of plasma concentrations of diazepam following administration of diazepam nasal spray, plasma concentrations were shown to be above approximately 70 ng/mL for the first 6 hours. ³⁴ Further study is needed on estimating therapeutic exposure based on threshold plasma levels for ISMs.

The long‐term safety study of diazepam nasal spray was an open‐label safety study, and there was no control or comparator group. ¹⁴ However, strengths include the large number of treated clusters (n = 3853) across an average exposure of about 1.5 years. ¹⁴ Diazepam nasal spray was permitted to follow an approval pathway that did not require a control owing to the proven agent diazepam and the approval of the reference formulation diazepam rectal gel, which was proven to be effective and to have an appropriate safety profile through randomized, placebo‐controlled trials. ³⁵ , ³⁶ In another study, diazepam nasal spray showed comparable bioavailability and lower variability in bioavailability than diazepam rectal gel. ²⁸ Although most of the presented analyses are post hoc, the data are from the largest database of treated seizure clusters.

7. CLINICAL RELEVANCE

The expert working group established by the Seizure Termination Project provided recommendations for therapies to be used for outpatient management of seizure clusters and prolonged seizures to prevent progression to a high‐level emergency. ¹² ACT therapies were recommended for preventing further seizures in a seizure cluster and REST for terminating an ongoing seizure. ¹² The findings presented here illustrate the application of the ACT/REST recommendations and demonstrate that the ISM diazepam nasal spray fulfills the consensus criteria for ACT and REST therapy and supports concepts behind the recent expert consensus terminology and recommendations for outpatient management of seizure clusters and prolonged seizures, including the importance of early treatment. ¹²

Timing to cessation of seizure clusters and prolonged seizures within a cluster was shown to be shorter with more rapid administration of diazepam nasal spray (i.e., <5 min vs. <2 min to administration), with effectiveness also demonstrated with later dosing. ¹⁰ Effectiveness of diazepam nasal spray across 24 h is supported by the low use of second doses. Interestingly, the use of second doses appeared to be somewhat higher for seizure clusters treated within the first 2 min; whether this might reflect caregivers' urgency to treat more severe seizure clusters is unknown.

8. CONCLUSIONS

Findings from the large dataset of the long‐term safety study of diazepam nasal spray demonstrate that it is of benefit in immediate use for termination of acute seizure clusters, prevention of further seizures in seizure clusters, and rapid termination of prolonged seizures within seizure clusters, supporting the recent expert consensus recommendations. Median treatment administration was 2 min, and termination was 3 min; administration at 5–15 min was still effective in cluster treatment (ACT). Even when diazepam nasal spray treatment was delayed, it terminated prolonged seizures in a cluster. Early use of a single rescue treatment can meet the need for ACT and REST, simplifying patient care.

There are potential benefits for having a single ISM that addresses both ACT and REST. A single treatment might reduce the time needed to educate patients and caregivers and could be less confusing during a seizure emergency, and potentially less time would be spent deliberating regarding which medication to use, preventing a delay in treatment. A single agent avoids the polypharmacy of drugs acting on the central nervous system (e.g., benzodiazepines); the potential for administering 2 different drugs with similar mechanisms of action for the treatment of a seizure emergency could lead to serious consequences.

Another endpoint that is important to patients and caregivers is the timing for patients to return to their usual selves and for care partners to return to their daily activities. These times to return to normal activities were low, irrespective of time to treatment, which might suggest a floor effect and should be interpreted with caution because of the small numbers of seizures treated in >5 minutes.

CONFLICT OF INTEREST STATEMENT

Dr. Chez has served as a consultant for and has received grant support and/or speaker or advisory honoraria from Aquestive Therapeutics; Catalyst; Eisai; GW Pharma; Jazz; Mallinckrodt; Zogenix; Marinus Pharmaceuticals; Neurelis, Inc.; and UCB Pharma. Dr. Klein has served as a consultant for Abbott; Arvelle Therapeutics; Neurelis, Inc.; SK Life Science; and UCB Pharma. He has served as a speaker for Aquestive Therapeutics; Eisai; Neurelis, Inc.; SK Life Science; Sunovion; and UCB Pharma. He has served on advisory boards for Alliance/Stratus; Aquestive Therapeutics; Arvelle Therapeutics; Eisai; Neurelis, Inc.; OB Pharma; SK Life Science; Sunovion; and UCB Pharma. He is the CEO of PrevEP, Inc., and has received research support from Lundbeck, the Department of Defense/CURE, and the National Institutes of Health Small Business Innovation Research. Dr. Becker is a consultant/speaker for Neurelis, Inc.; SK Life Science; and Jazz Pharmaceuticals. Dr. Peters has served as a speaker and consultant for Neurelis, Inc. Dr. Carrazana is an employee of and has received stock and stock options from Neurelis, Inc. Dr. Rabinowicz is an employee of and has received stock options from Neurelis, Inc. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Supporting information

Figure S1.

Appendix S1.

Chez M, Klein P, Becker D, Peters JM, Carrazana E, Rabinowicz AL. Exploring proposed recommendations for immediate‐use seizure medication: Treating both cluster and prolonged seizures with diazepam nasal spray. Epilepsia Open. 2025;10:999–1008. 10.1002/epi4.70054

DATA AVAILABILITY STATEMENT

Research data are not shared.