Intermittent and repeated exposure to midazolam administered as a single‐dose nasal spray (MDZ‐NS) was generally well tolerated and effective for terminating seizures within 10 minutes in a large proportion of patients who experienced seizure clusters, according to findings from a study published in Epilepsia.
The study was part of an open-label extension trial (ClinicalTrials.gov identifier: NCT01529034) that enrolled patients aged ≥12 years who had an epilepsy diagnosis (focal or generalized) and a history of seizure clusters (n=175). Patients included in the open-label extension phase were on a stable treatment regimen consisting of antiepileptic drugs and had completed the original phase 3 trial.
In the event of seizure clusters that did not terminate within 10 minutes, caregivers administered MDZ‐NS at a dose of 5 mg. A second dose was administered if seizures did not terminate within 10 minutes following the initial dose or if seizures recurred in 10 minutes to 6 hours following the initial dose. A rescue protocol was initiated by caregivers if seizure activity persisted following the second MDZ‐NS dose. Treatment success was defined as no recurrence of seizure in >10 minutes and ≤6 hours of administration.
Treatment success, or seizure termination within 10 minutes and no recurrence within 10 minutes to 6 hours after administration of MDZ-NS, comprised the main seizure-related outcome (ie, treatment success). During this phase of the study, investigators also monitored patients for treatment‐emergent adverse events.
Approximately 92% (n=161) of the cohort received ≥1 dose of MDZ‐NS, representing a total of 1998 seizure cluster episodes during the trial (median, 16.8 months [range, 1‐55.7 months). Treatment‐emergent adverse events were experienced by 40.4% of patients within 2 days of treatment; 57.1% experienced a treatment-emergent adverse event at some point over the course of the trial. The most common adverse events reported during the course of the study included nasal discomfort (12.4%) and somnolence (9.3%). These events caused 2 patients to discontinue treatment.
For the first MDZ-NS treatment dose, treatment success was achieved in 55.5% (n=1108) of seizure cluster episodes (95% CI, 53.2%‐57.7%). The median episode treatment success for this dose was 54.2% (range, 0%‐100%). For the first treated cluster, 87.6% (95% CI, 81.5‐92.2) of patients experienced seizure termination within 10 minutes of the first dose. Further, 69.0% (95% CI, 61.8‐76.6) had no recurrence of seizure within the 10-minute to 6-hour window following treatment with MDZ‐NS. Treatment success was achieved in 80.2% (n=617) of seizure clusters following the second dose.
Limitations of the study included the open-label design as well as the lack of a comparator control group.
The researchers concluded that MDS-NS was safe and tolerable in the acute treatment of seizure clusters. They further suggest that in addition to “the ease and social acceptability of intranasal administration, MDZ‐NS represents a promising option for the outpatient treatment of patients requiring acute therapeutic intervention for [seizure clusters].”
Disclosure: Several of the study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Wheless JW, Meng TC, Van Ess PJ, Detyniecki K, Sequeira DJ, Pullman WE. Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters: an open-label extension trial [published online July 29, 2019]. Epilepsia. doi:10.1111/epi.16300