A critical evaluation of midazolam nasal spray for the treatment of patients with seizure clusters

Figures & data

Table 1. Pharmacokinetics, availability, and indications of MDZ-NS, buccal MDZ, and intramuscular MDZ

	MDZ-NS [44]	Buccal MDZ (Buccolam®) [43]	Buccal MDZ (Epistatus®) [42]	Intramuscular MDZ (Seizalam™) [41]
Pharmacokinetic parameters
Tmax	17.3 min for single 5-mg dose in healthy adults	≤30 min in children	≤30 min	30 min for single 10-mg dose in healthy volunteers
Cmax	54.7 ng/mL for single 5-mg dose in healthy adults	148 ng/mL for 5 mg in children aged 1 to <5 years	-	113.9 ng/mL for single 10-mg dose in healthy volunteers
AUC0–∞	126.2 ng·h/mL for single 5-mg dose in healthy adults	242 ng·h/mL for 5 mg in children aged 1 to <5 years	-	402.7 ng·h/mL for single 10-mg dose in healthy volunteers
Bioavailability	~44%	75% in adults, 87% in children with severe malaria and convulsions	75% in healthy adults, 87% in children with severe malaria and convulsions	-
Volume of distribution	226.5 L	5.3 L/kg	5.3 L/kg	2.1 L/kg for single 10-mg dose in healthy volunteers
T½	2.1–6.2 h	Initial: 0.45 h, terminal: 3.4 h	0.8–1.8 h in children aged >12 months, 1.7–2.6 h in adults	4.2 h for 10-mg dose
Availability	United States	Europe	United Kingdom	United States
Indication	Acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e. SCs, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 12 years of age and older	Treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents with epilepsy aged 3 months to <18 years	Treatment of prolonged, acute, convulsive seizures in children and adolescents with epilepsy aged 10 to <18 years	Treatment of SE in adults

AUC_0–∞, area under the plasma concentration–time curve from time zero to infinity; C_max, peak plasma drug concentration; MDZ, midazolam; MDZ-NS, midazolam nasal spray; SC, seizure cluster; SE, status epilepticus; T_½, elimination half-life; T_max, time to reach peak plasma concentration after drug administration.

Table 2. Summary of data from phase I and phase III trials of MDZ-NS

Trial	Group	Safety and tolerability outcomes					Efficacy outcomes
		≥1 TEAE, n (%) or % only	≥1 treatment‐related TEAE, n (%)	≥1 serious TEAE, n (%)	≥1 treatment‐related serious TEAE, n (%)	Discontinuation due to TEAE, n (%)	Treatment success^a, % (95% CI)	Documented return to full baseline functionality within 24 hours after administration of MDZ‐NS^b, % (95% CI)
Phase I trials
In adults with epilepsy (data on file)	MDZ-NS 10 mg (n = 12)	12 (100)	12 (100)	0	0	0	-	-
	MDZ-NS 15 mg (n = 12)	12 (100)	12 (100)	0	0	0	-	-
	MDZ-NS 17.5 mg (n = 12)	11 (91.7)	11 (91.7)	0	0	0	-	-
	MDZ-NS 20 mg (n = 12)	12 (100)	11 (91.7)	0	0	0	-	-
	PBO (n = 12)	10 (83.3)	9 (75.0)	0	0	0	-	-
In healthy adults [53] and data on file	Age ≥65 years, MDZ-NS 2.5 mg (n = 18)	14 (77.8)	14 (77.8)	0	0	0	-	-
	Age ≥65 years, MDZ-NS 5 mg (n = 18)	15 (83.3)	15 (83.3)	0	0	0	-	-
	Age 18–40 years, MDZ-NS 2.5 mg (n = 12)	7 (58.3)	6 (50.0)	0	0	0	-	-
	Age 18–40 years, MDZ-NS 5 mg (n = 12)	8 (66.7)	8 (66.7)	0	0	0	-	-
In pediatric (2–13 years) patients with epilepsy [64]	MDZ-NS 1.25 mg (n = 12)	9 (75.0)	8 (66.7)	1 (8.3)	0	0	-	-
	MDZ-NS 2.5 mg (n = 12)	9 (75.0)	8 (66.7)	0	0	0	-	-
	MDZ-NS 5 mg (n = 12)	7 (58.3)	7 (58.3)	0	0	0	-	-
Phase III trials
ARTEMIS-1 (patients ≥12 years of age) comparative phase [54]	DB MDZ-NS only (n = 91)	24 (26.4)	20 (22.0)	1 (1.1)	0	0	-	-
	DB MDZ-NS+OL MDZ-NS (n = 43)	13 (30.2)	13 (30.2)	0	0	0	-	-
	DB PBO only (n = 26)	6 (23.1)	5 (19.2)	0	0	0	-	-
	DB PBO+OL MDZ-NS (n = 41)	9 (22.0)	7 (17.1)	1 (2.4)	0	0	-	-
	MDZ-NS group^c (n = 134)	-	-	-	-	-	53.7 (45.3–62.2) p = 0.0109 vs. PBO (two-sided test)	72.4 (64.0–79.8) p < 0.0001 vs. PBO
	PBO group^d (n = 67)	-	-	-	-	-	34.3 (23.0–45.7)	43.3 (31.2–56.0)
ARTEMIS-2 (patients ≥12 years of age) [56]	All patients (n = 161)	92 (57.1)	57 (35.4)	18 (11.2)	4 (2.5)	4 (2.5)	55.5 (53.2–57.7)^e	74.0 (72.0–75.9)^e

^aTreatment success was a composite measure defined as seizure termination within 10 minutes of, and no seizure recurrence 10 minutes to 6 hours after, DB administration of trial drug (in ARTEMIS-1) or administration of the first dose of MDZ-NS (in ARTEMIS-2 [OL extension to ARTEMIS-1]).

^bAfter DB dose in ARTEMIS-1 and after the first MDZ-NS dose in ARTEMIS-2.

^cPatients who received DB MDZ-NS only or DB MDZ-NS followed by an OL MDZ-NS dose.

^dPatients who received DB PBO only or DB PBO followed by an OL MDZ-NS dose.

^ePercentage of seizure cluster episodes.

CI, confidence interval; DB, double-blind; MDZ-NS, midazolam nasal spray; OL, open-label; PBO, placebo; TEAE, treatment-emergent adverse event.

UCB, Inc. NAYZILAM® (midazolam) nasal spray, CIV US prescribing information. 2019. [cited 2020 Feb 17]. Available from: https://www.ucb-usa.com/_up/ucb_usa_com_kopie/documents/Nayzilam_PI.pdf

 Google Scholar

Shire Services BVBA. BUCCOLAM summary of product characteristics. 2019. [cited 2020 Aug 20]. Available from: https://www.ema.europa.eu/en/documents/product-information/buccolam-epar-product-information_en.pdf

 Google Scholar

Veriton Pharma Ltd. Epistatus® summary of product characteristics. 2019. [cited 2020 Aug 21]. Available from: https://www.epistatus.co.uk/downloads/epistatus_summary_of_product_characteristics.pdf

 Google Scholar

Meridian Medical Technologies I. Seizalam™ prescribing information. 2018. [cited 2020 Aug 21]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209566Orig1s000lbl.pdf

 Google Scholar

Berg AK, Myrvik MJ, Van Ess PJ. Pharmacokinetics, pharmacodynamics, and tolerability of USL261, midazolam nasal spray: randomized study in healthy geriatric and non-geriatric adults. Epilepsy Behav. 2017;71:51–59.

 PubMed Web of Science ®Google Scholar

Bancke L, Meng T-C, Kapelan B, et al. Tolerability of midazolam nasal spray in pediatric subjects with epilepsy. 70th American Epilepsy Society Annual Meeting; December 2–6; Houston, TX; 2016 (abstract 2.197).

 Google Scholar

Detyniecki K, Van Ess PJ, Sequeira DJ, et al. Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters - a randomized, double-blind, placebo-controlled trial. Epilepsia. 2019;60:1797–1808.

 PubMed Web of Science ®Google Scholar

Wheless JW, Meng TC, Van Ess PJ, et al. Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters: an open-label extension trial. Epilepsia. 2019;60:1809–1819.

 PubMed Web of Science ®Google Scholar

Data availability statement

Due to the small sample size in trials P261-201 and P261-102, individual patient-level data cannot be adequately anonymized as there is a reasonable likelihood that individual participants could be re-identified. For this reason, data from these trials cannot be shared.

Underlying data from the ARTEMIS-1 and ARTEMIS-2 trials included in this manuscript may be requested by qualified researchers 6 months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized individual patient-level data and redacted trial documents which may include: analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password protected portal.