Seizure cluster: Definition, prevalence, consequences, and management

Objective: To assess pharmacokinetics and safety of diazepam nasal spray (NRL-1; VALTOCO®) in pediatric and adult patients with epilepsy in seizure and nonseizure states. Methods: A single dose of diazepam nasal spray (5, 10, 15, or 20 mg based on weight) was administered during each of two conditions (ictal/peri-ictal and interictal condition) to patients 6-65 years old with partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness; a second dose was permitted if needed for persistent seizures. Dosing could be interictal or ictal/peri-ictal first, with a washout of ≥14 days. Blood samples for pharmacokinetic analysis were taken at prespecified time points. Treatment-emergent adverse events (TEAEs), sedation, nasal irritation, nasal mucosal pain, and olfactory changes were assessed. Results: Of 57 patients in the study (mean age = 28.1 years [range = 6-59], 54.4% female, 80.7% white), 49 were included in the primary pharmacokinetic analyses. Diazepam pharmacokinetic profiles were similar under both conditions, with approximately 2-hour median time to mean (SD) maximum plasma concentrations of 164 (88) and 189 (110) ng/mL for ictal/peri-ictal and interictal conditions, respectively; drug exposure during the first 6 hours postdosing was 532 (313) and 615 (368) h•ng/ mL, respectively. Seventeen patients (29.8%) reported TEAEs, of whom eight (14%)had treatment-related TEAEs, with those reported in ≥2 patients being dysgeusia (n = 3, 5.3%) and nasal discomfort (n = 2, 3.5%). One patient had serious TEAEs (recurrent seizures, metabolic encephalopathy), which were deemed unrelated to study treatment. No changes in respiratory rate were observed, nor were there clinically relevant changes in sedation, olfaction, nasal irritation, or acute nasal mucosal pain.

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and safety of VALTOCO (NRL‐1; diazepam nasal spray) in patients with epilepsy during seizure (ictal/peri‐ictal) and nonseizure (interictal) conditions: A phase 1, open‐label study

Hogan

Tarquinio²,

Sperling

et al. 2020

“…Most SCs occur outside of hospitals, typically necessitating acute intervention to minimize adverse sequelae, including potentially life‐threatening status epilepticus . Intravenous benzodiazepines, the mainstay of treatment in seizure emergencies, cannot be administered by non–health care professionals (HCPs).…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4] Most SCs occur outside of hospitals, typically necessitating acute intervention to minimize adverse sequelae, including potentially life-threatening status epilepticus. [5][6][7] Intravenous benzodiazepines, the mainstay of treatment in seizure emergencies, cannot be administered by non-health care professionals (HCPs). Diazepam rectal gel (PR-DZP) is the only drug approved for out-of-hospital administration in the United States, 8 and buccal midazolam (MDZ) is approved for use in children in some European countries.…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters—a randomized, double‐blind, placebo‐controlled trial

Detyniecki¹,

Ess²,

Sequeira³

et al. 2019

Self Cite

129

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.

“…Seizures in a cluster may also differ in type, duration, or severity from patients’ typical seizures . Given the wide variation in the number of seizures in a given cluster and the timeframe within which they occur, a consensus definition remains elusive …”

Section: Introductionmentioning

confidence: 99%

“…3,4 Given the wide variation in the number of seizures in a given cluster and the timeframe within which they occur, a consensus definition remains elusive. 5 Seizure clusters may necessitate acute therapeutic intervention to prevent progression to adverse, serious sequelae. Because most patients experience SCs outside of hospitals, therapeutic agents are required that can be administered by non-health-care professionals in the outpatient setting.…”

mentioning

confidence: 99%

Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters: An open‐label extension trial

Wheless

Meng²,

Ess³

et al. 2019

Self Cite

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.