Safety and efficacy of midazolam nasal spray for the treatment of intermittent bouts of increased seizure activity in the epilepsy monitoring unit: A double-blind, randomized, placebo-controlled trial.

OBJECTIVE: Midazolam nasal spray (MDZ-NS) is indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern, in patients 12 years of age and older with epilepsy. This trial evaluated safety and efficacy of MDZ-NS in patients with epilepsy who were admitted to the epilepsy monitoring unit for seizure characterization/presurgical evaluation. METHODS: In this randomized, double-blind, placebo-controlled phase 3 trial (P261-301; NCT01999777), eligible patients with ≥2 seizures in the 6-hour window preceding trial medication administration for whom treatment was appropriate based on investigator's judgment were randomized (1:1) to MDZ-NS 5 mg or placebo. Efficacy outcomes were proportion of patients seizure-free for 6 hours after treatment and time to first seizure within 6 hours. Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs). RESULTS: Sixty-two patients were randomized (MDZ-NS n = 31; placebo n = 31), received trial medication, and completed the trial. A higher proportion of patients on MDZ-NS than placebo were seizure-free for 6 hours following treatment (54.8% vs 38.7%); however, the 16.1% difference was not statistically significant (P = .1972). The Kaplan-Meier curve of time to first seizure showed separation of both groups in favor of MDZ-NS from ~1.5 hours post-dose and throughout the 6-hour Treatment phase. Median time to first seizure was not estimable for MDZ-NS (>50% of patients had no seizure) and 3.9 hours for placebo (P = .1388). TEAEs with MDZ-NS were generally comparable to those with placebo. There were no deaths, serious TEAEs, or discontinuations due to TEAEs. SIGNIFICANCE: Although the observed treatment difference may be clinically meaningful, statistical significance was not demonstrated. Results suggest that MDZ-NS 5 mg may provide improvement over placebo, with efficacy maintained for ≥6 hours post-dose. MDZ-NS was well tolerated in this population.

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

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.

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

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.

Pharmacokinetics, pharmacodynamics, and tolerability of USL261, midazolam nasal spray: Randomized study in healthy geriatric and non-geriatric adults.

AIM: Characterize pharmacokinetics, pharmacodynamics, and safety/tolerability of USL261 in geriatric adults to inform its potential for treating bouts of increased seizure activity. METHODS: Phase 1, randomized, double-blind, 2-way crossover study in healthy geriatric (≥65years; n=18) and non-geriatric (18-40years; n=12) adults evaluated single USL261 doses (2.5 and 5.0mg) administered intranasally. Pharmacokinetic parameters were estimated for midazolam and 1-hydroxymidazolam (active metabolite), including area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), time to Cmax (Tmax), and half-life (t1/2). Stanford Sleepiness Scale and Observer's Assessment of Alertness/Sedation assessed sedation; Digit-Symbol Substitution Test assessed psychomotor performance. RESULTS: Midazolam exposure and plasma concentrations were higher in geriatric versus non-geriatric adults (geometric mean AUC0-∞ [ng*h/mL] 2.5mg: 70 vs 54, respectively; 5.0mg: 157 vs 110; Cmax [ng/mL] 2.5mg: 27.1 vs 22.5; 5.0mg: 55.8 vs 46.1). USL261 was rapidly absorbed, with no differences in median Tmax (14.5-17.3min); mean t1/2 was longer in geriatric subjects. Similar age-related trends were observed for 1-hydroxymidazolam. Mean maximum observed pharmacodynamic effects were not significantly different between age groups, though were more pronounced following 5.0 versus 2.5mg (P<.05); return to baseline was generally achieved within 4h. USL261 was generally well tolerated, with similar adverse event rates between age groups. CONCLUSIONS: Despite increased midazolam exposure in geriatric subjects, there were no differences between age groups in pharmacodynamic effects or adverse event rates. USL261 was rapidly absorbed and pharmacodynamic effects returned to baseline within ~4h, regardless of age. Dose-dependent pharmacokinetic and maximum pharmacodynamic effects were observed. Overall, pharmacokinetic findings for USL261 were similar to studies evaluating intravenous midazolam, whereas pharmacodynamic effects were less pronounced in the elderly than previously reported.

Clinical pharmacokinetic and pharmacodynamic profile of midazolam nasal spray.

The benzodiazepine midazolam (MDZ) is commonly used as first-line treatment in patients with acute seizures. This review summarizes the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MDZ nasal spray (MDZ-NS), which can be administered by non-health care providers in the outpatient, ambulatory setting. Intranasal administration leads to rapid (tmax 9.0-21.5 min), consistent, and extensive absorption of MDZ, with fast distribution to the central nervous system (CNS), as demonstrated by the onset of sedation within 10 min after administration and the occurrence of peak psychomotor impairment at approximately 17-120 min after administration. Rapid plasma clearance of MDZ and its active metabolite 1-OH-MDZ (t½ 3.6-8.1 h) results in a return to baseline alertness and psychomotor functionality by approximately 240 min post dose. The lack of first-pass metabolism reduces the potential for drug-drug interactions compared with oral dosing. Age (≥ 12 years), sex, race, body weight, body mass index, normal to moderately impaired renal function, and concomitant administration of cytochrome P450 (CYP)3A-inducing drugs are not considered important factors for MDZ-NS dosing. However, coadministration of MDZ-NS with moderate or strong CYP3A4 inhibitors should be avoided, and MDZ-NS should be used with caution when coadministered with mild CYP3A4 inhibitors, as these may result in prolonged MDZ effects owing to a decrease in plasma clearance. Taken together, the PK and PD properties of MDZ-NS, with a short tmax that translates into rapid CNS PD effects of sedation and psychomotor impairment, demonstrate rapid CNS penetration and onset of action, supporting its use for acute treatment of seizure clusters.

Enhanced induction of cytochrome P450 enzymes and CAR binding in TNF (p55(-/-)/p75(-/-)) double receptor knockout mice following phenobarbital treatment.

Phenobarbital (PB) is a well characterized inducer of cytochrome P450 (P450) 2B and 3A subfamilies. Several proinflammatory cytokines have been shown to negatively modulate the induction of P450 by PB. In addition, PB is known to elicit an inflammatory mitogenic effect on the liver. To date, no studies have evaluated the PB induction profile of hepatic P450 in the absence of an intact tumor necrosis factor-alpha (TNFalpha) response. To test the hypothesis that endogenous TNFalpha signaling modulates hepatic P450 induction by PB in vivo, PB induction was examined in TNF (p55(-/-)/p75(-/-)) double receptor knockout mice (ko-TNF) and wild-type mice (wt-TNF). CYP2B- and CYP3A-associated activities and protein content were induced to a significantly greater extent (p < 0.05) in ko-TNF mice compared with wt-TNF mice. In parallel with enhanced CYP2B induction, an apparent elevation in the nuclear accumulation of the principal regulatory protein for transcription of CYP2B genes, the constitutively activated receptor (CAR), was detected in ko-TNF nuclear extracts following PB treatment. Additionally, nuclear factor kappa-B binding was induced by PB in wt-TNF mice, but not in ko-TNF mice, indicating that the hepatic inflammatory response following PB treatment differed between wt-TNF and ko-TNF mice. These data demonstrate that endogenous TNFalpha signaling modulates PB induction of hepatic CYP2B and CYP3A isoforms in vivo. Further, the data presented herein suggest that endogenous TNFalpha signaling influences PB induction of CYP2B through inhibition of CAR nuclear accumulation.