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

ABSTRACT

Introduction: Patients with epilepsy may experience seizure clusters (SCs), which are considered a medical emergency requiring immediate treatment. Besides seizures and seizure-related injuries, patients with SCs experience impaired quality of life and have a greater need for healthcare resources. Midazolam nasal spray (MDZ-NS) was approved by the United States Food and Drug Administration (FDA) for the treatment of SCs in 2019, and was the first FDA-approved nasally administered formulation for treating SCs.

Areas covered: This article provides a critical evaluation of MDZ-NS for the treatment of patients with SCs. It covers the chemistry, pharmacodynamic and pharmacokinetic properties of MDZ-NS, and safety, tolerability, and efficacy data from phase I and phase III trials. SC treatment guidelines in different countries and for alternative therapies are also discussed.

Expert opinion: Midazolam is a well-established drug that is familiar to physicians. The newer MDZ-NS formulation offers the benefits of intranasal administration, which allows for outpatient treatment by caregivers and other non-healthcare professionals when an SC occurs, and may be particularly meaningful to patients with limited treatment options because other routes of administration are unsuitable. MDZ-NS is effective and patients are known to return to baseline alertness and psychomotor function within 240 minutes after administration.

KEYWORDS:

• Acute seizures
• epilepsy
• intranasal midazolam
• rescue therapy
• seizure clusters

1. Introduction

1.1. Demography

Patients with epilepsy may experience seizure clusters (SCs), which manifest as acute episodes of repetitive seizures with short inter-ictal periods [1,2]. Considered a medical emergency that should be treated immediately, SCs include all epileptic seizure types and may vary in severity [3]. SC episodes can evolve into status epilepticus (SE) [2,4–6], but are not consistently associated with mortality [5,7].

Although SCs can occur at any age [3], the mean adult age ranges from 33 to 41 years [6,8–11]. SC prevalence ranges from approximately 3% to 57.1% in patients with epilepsy, across all age groups [5–7,12–171517]. This wide variation in prevalence is likely because of differences in epilepsy type, seizure severity and frequency, clinical SC definition, study type, and setting reported. The highest prevalence (57.1%) was reported by a statistical analysis of seizure diaries in 63 patients with treatment-resistant focal epilepsy [12], while the lowest (approximately 3%) was reported by a historical cohort study of 21,010 patients with active epilepsy in the United Kingdom (UK), which defined SCs as three or more partial or generalized seizure episodes over a 24-hour period [14].

Risk factors for SCs include high seizure frequency [2,6,7,18], history of SE [2,4–6], and use of a higher number of antiepileptic drugs (AEDs) [2,5,7]. In females, SCs may occur in alignment with certain phases of the menstrual cycle [19]. Failure of adequate trials of two tolerated, appropriately chosen, and used AED schedules (alone or in combination) to achieve sustained seizure freedom constitutes drug-resistant epilepsy, as defined by the International League Against Epilepsy (ILAE) [20]. Among patients who have failed two or more AEDs, 17.4% experience SCs [5]. The prevalence of drug resistance in patients with epilepsy was estimated as 30% in a systematic review and meta-analysis, although only one of the eight studies contributing to the pooled estimate fulfilled the ILAE definition [21]. Although not all patients who experience SCs may also be resistant to treatment, applying the above figures to 3.4 million people with active epilepsy in the United States (US) [22] suggests that an estimated 177,000 patients with drug-resistant epilepsy may experience SCs.

Prospective observational data in adults with SCs report a frequency of 12.7 SC episodes per year [6]. Patients with SCs during treatment are four times more likely to experience drug-resistant epilepsy than patients without SCs, although 58% of these patients may achieve seizure freedom for at least 5 consecutive years anytime in the course of treatment [7].

1.2. Unmet medical need and burden

There is no agreed definition of SCs, hindering their identification [2]. Definitions include three or more seizures within 24 hours, two or more seizures within 24 hours, and two or more seizures within 6 hours [2,6]. Hence, SCs are poorly recognized, understudied, and undertreated [23]. The importance of improving recognition and understanding of SCs is paramount to their treatment, particularly in light of new therapies and delivery methods.

Alongside the burden of experiencing seizures and seizure-related injuries [6], patients with SCs experience impaired quality of life and have a greater need for healthcare resources [2]. In a survey, 31% of patients with epilepsy or a seizure disorder who had experienced SCs and 40% of caregivers providing current care for a patient with SCs reported using an emergency room (ER) for SCs in the previous year [10]. There are no cost data for SCs. However, in treatment-adherent, previously seizure-free patients with epilepsy who were treated in the inpatient/ER setting for new-onset seizures, epilepsy-related ER visits during 6-month follow-up were associated with a median cost of 181 USD per person (2012 US dollars) [24]. Patients and caregivers report that SCs negatively affect many facets of patients’ lives including the ability to drive, work, live independently, and participate in social or extracurricular activities, in addition to causing a financial burden [10].

1.3. Treatment guidelines

There are currently no guidelines on the treatment of SCs in the US. The American Academy of Neurology and American Epilepsy Society have published joint guidelines on epilepsy treatment in general, but these do not include specific guidance on SCs [25,26]. In other countries, three guidelines incorporate the management of SCs: the guidelines of the National Institute for Health and Care Excellence (NICE) in the UK [27], the Scottish Intercollegiate Guidelines Network (SIGN) in Scotland, UK [28], and the Hospital Authority Pediatric Coordinating Committee, Quality Assurance Subcommittee, Working Group on Guideline and Evidence Based Practice in Hong Kong [29].

The options for treating SCs differ between countries. The above-mentioned guidelines all recommend the use of buccal midazolam (MDZ) and rectal diazepam [27–29]. The SIGN and Hong Kong guidelines also recommend intranasal MDZ [28,29]. The NICE guideline considers intravenous (IV) lorazepam [27] and the Hong Kong guideline also considers rectal lorazepam [29].

2. Market overview

2.1. Unmet needs of currently available therapies

Optimal therapies for patients with epilepsy who experience SCs should be effective for different seizure types with few adverse effects, act rapidly, and be easily administered by a caregiver. The method of delivery should be practical, enabling rapid administration in varying settings, and without the patient’s assistance.

Available medications are limited as they are for in-hospital administration by healthcare professionals only, are unsuitable for frequent use, or do not provide a delivery method that is convenient and acceptable to patients in the community. A main concern to patients and caregivers is rectal administration, which carries the drawbacks of embarrassment, being socially unacceptable, particularly when given in a public setting, can be difficult to administer in some situations, and has potential legal implications [30].

Rescue medications (RMs) play an important role in SC management, but are preferably avoided in favor of treatment in the ER [10]. Reasons for avoiding RMs include issues with their administration (concerns with rectal administration; difficulty in self-administration; and requirement for caregiver-administration) and poor physician–patient communication, with patients not recognizing an SC and a lack of seizure action plans [5,10]. There is ample evidence showing that patients, families, and caregivers prefer non-rectal routes of administration [31–3534], which suggests that having a non-rectal formulation could increase the use of RMs.

In adult patients with epilepsy, RM prescription is predicted by a young age at onset, active epilepsy, structural etiology, presence of generalized tonic-clonic seizures, past medical history of SE, and living with another person [36]. In pediatric patients with epilepsy, the predictors are a history of SE and an average seizure duration of longer than 30 seconds [33]. The same study showed that among the patients with a prescribed RM, only 61% of the families received training on how to administer the drug [33]. Therefore, insufficient training may also contribute to the underutilization of RMs.

2.2. Alternative treatments in the clinic, in late development, and in the community

Treatment options for SCs include extra doses of antiepileptic medication, oral benzodiazepines such as diazepam, clonazepam, or lorazepam (for when seizures do not occur too closely together in a cluster), parenteral benzodiazepines (for in-hospital treatment administered by healthcare professionals), and rectal diazepam gel and buccal/intranasal benzodiazepines (for use in the community, administered by patients themselves and caregivers) [2,3,37,38]. Other means of treatment and delivery have been explored in light of treatment constraints, including intramuscular diazepam autoinjectors, intramuscular MDZ, and inhaled alprazolam [2,3,39].

Intramuscular MDZ is a traditional and well-known route of administering MDZ, and various formulations are available [40], including one approved in 2018 by the US Food and Drug Administration (FDA) for treating SE in adults that is only for use by healthcare professionals (Table 1) [41]. In addition to the requirement for training, this delivery method is associated with pain and a risk of infection [40]. Buccal MDZ is easier to use and painless, but absorption can be unpredictable and any drug that is swallowed is subject to first-pass metabolism [40]. Two buccal MDZ formulations, Buccolam® and Epistatus®, were approved for the treatment of prolonged seizures, in 2011 and 2017, respectively (Table 1) [38,42]. Buccolam® is available in Europe, while Epistatus® is available solely in the UK. Both drugs are only licensed for children and adolescents [38,42,43]. Rectal diazepam was the only formulation approved for treatment in the community by the FDA until MDZ nasal spray (MDZ-NS) was approved for SCs in 2019, for patients with epilepsy 12 years of age and older [44,45]. Since then, in 2020, diazepam nasal spray has also been approved by the FDA for acute treatment of SCs outside of the medical setting, for patients with epilepsy 6 years of age and older [46,47].

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.

3. Introduction to the drug

3.1. Chemistry

A preliminary intranasal formulation of MDZ to treat SCs was developed by Ikano Therapeutics. Upsher-Smith later acquired the drug from Ikano Therapeutics and reformulated the inactive ingredient concentration ratios and changed the nasal applicator. The resulting intranasal formulation of MDZ is optimized for single-dose delivery, and is available as a combination product along with the delivery device. It is this current formulation (MDZ-NS) that is approved by the FDA for the treatment of SCs and is the focus of this drug profile. The pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the Ikano Therapeutics nasal spray formulation are reported elsewhere [48].

MDZ is a member of the benzodiazepine class [44,45], and specifically an imidazobenzodiazepine, chemically designated as 8-chloro-6-(ο-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine. It has the molecular formula C₁₈H₁₃ClFN₃ and a molecular weight of 325.8. MDZ is a white or yellowish, crystalline solid, which is mostly insoluble in water but soluble in methanol, acetone, and alcohol. MDZ-NS is a clear, colorless/yellowish liquid, with a pH of approximately 5.0–9.0. Each single-dose unit of MDZ-NS delivers 5 mg of MDZ in 0.1 mL of solution containing ethanol, PEG-6 methyl ether, polyethylene glycol 400, propylene glycol, and purified water.

3.2. Nasal applicator

The volume of drug that can be delivered intranasally is limited to a few hundred microliters, since each nostril can only hold 150–200 µL of administered drug [49]. For this reason, intranasal administration requires a high drug concentration to optimize dosing volumes and relies on a delivery technology such as an atomizer to achieve effective drug absorption [40]. The nasal applicator used with MDZ-NS is a known nasal spray (Aptar DMF 24109) that is similar to those used for intranasal diazepam and sumatriptan.

3.3. Pharmacodynamics

The mechanism of action of MDZ is not fully elucidated. Typical to the benzodiazepines, MDZ binds to the benzodiazepine site of the gamma-aminobutyric acid A receptor in the central nervous system, which results in increased chloride permeability and decreased neuronal excitability [50]. The PD properties of MDZ and its metabolites are similar to those of other benzodiazepines and include sedative, hypnotic, anxiolytic, muscle relaxant, and amnestic activities [45].

Brain entry of intranasal MDZ preparations has been investigated by electroencephalography (EEG) in healthy volunteers [51] and in patients with SE [52]. In both groups, β-band changes were already evident at 4–7 minutes after drug administration. It is important to note that these intranasal MDZ preparations are different from MDZ-NS.

3.3.1. Sedation

Sedation following MDZ-NS administration was dose dependent in healthy elderly and younger adult volunteers [48,53], although a clear dose–response was not observed in adults with epilepsy [48]. In healthy volunteers, sedation following MDZ-NS 2.5 mg or 5 mg had a rapid onset, peaking at 14–52 minutes on the Stanford Sleepiness Scale (SSS) and at 15–30 minutes on the Observer’s Assessment of Alertness/Sedation scale (OAA/S) sum score [53], and returning to near-baseline levels by approximately 240 minutes post dose [53]. More pronounced sedation was observed with MDZ-NS 5 mg versus 2.5 mg, but there were no differences in the time to return to baseline values [53]. At the same dose level, there were no significant differences in sedation between elderly and younger adults [53].

Peak effects on the SSS and OAA/S occurred within 15–120 minutes following MDZ-NS 5 mg or 10 mg (2 × 5-mg doses) in healthy adults, adults with epilepsy, and adolescents and adults with epilepsy and a history of SCs [48]. In ARTEMIS-1 (ClinicalTrials.gov NCT01390220), a phase III, randomized, double-blind, placebo-controlled trial that evaluated MDZ-NS in patients (≥12 years of age) experiencing SCs [54], peak effects on the OAA/S were observed at approximately 30 minutes post MDZ-NS 10 mg (2 × 5-mg doses) in the test dose phase of the trial [48]. In the comparative phase of the trial, a higher proportion of patients treated with MDZ-NS 5 mg than placebo-treated patients had documented return to baseline functionality within 24 hours after double-blind drug administration (72.4% vs. 43.3%, p < 0.0001; Table 2) [54]; the median time to return to baseline functionality was 92 (interquartile range 50–224) minutes in MDZ-NS-treated patients reporting somnolence [48,55]. In the open-label extension to ARTEMIS-1, ARTEMIS-2 (ClinicalTrials.gov NCT01529034), patients returned to full baseline functionality at a median of 72 (interquartile range 30–180) minutes after receiving MDZ-NS 5 mg [56].

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.

3.3.2. Psychomotor impairment

The time to peak psychomotor impairment (T_effect) for baseline-adjusted Digit Symbol Substitution Test trial completion rate and percent correct values was approximately 17–120 minutes [48,53], and generally earlier in elderly versus younger adult volunteers [53]. Psychomotor impairment was transient and return to baseline function occurred within 240 minutes post dose [48,53]. Peak effects were greater following MDZ-NS 5 mg versus 2.5 mg, but were not significantly different between elderly and younger participants.

In adults with epilepsy, psychomotor impairment was evaluated using the Wechsler Adult Intelligence Scale-IV (WAIS-IV) [48]. The effects were not dose dependent and peaked at 20 minutes following a single dose of MDZ-NS 15–20 mg, with scores returning to baseline levels within 240 minutes post dose. The median time to return to baseline psychomotor function is not currently available.

3.3.3. Abuse liability

MDZ is a controlled substance in the US and other countries because of its potential for abuse. In the US, MDZ is a Schedule IV drug, which is defined as a drug with a low potential for abuse and low risk of dependence [57]. In healthy, adult, recreational benzodiazepine users, the abuse potential of MDZ-NS was similar to that of oral MDZ syrup, with no differences in subjective positive effects at equivalent doses, as indicated by median Drug Liking Visual Analog Scale (VAS) maximum effect (E_max), Overall Drug Liking VAS E_max, and High VAS E_max [58].

3.3.4. Interaction with opioids

Concomitant use of benzodiazepines, such as MDZ-NS, and opioids may lead to profound sedation, respiratory depression, coma, and death [44]. The risk of respiratory depression is increased because benzodiazepines and opioids act at different receptor sites in the central nervous system that control respiration. Observational studies have demonstrated an increased risk of drug-related mortality when benzodiazepines and opioids are taken together compared with the use of opioids alone [44]. Consequently, the US Prescribing Information for MDZ-NS recommends reserving concomitant prescribing of benzodiazepines and opioids for patients with inadequate alternative treatment options, as well as limiting dosages and durations of concomitant use to the minimum required. In addition, the patients should be followed closely for signs and symptoms of respiratory depression and sedation.

3.4. Pharmacokinetics

The PK of MDZ-NS has been established in phase I trials conducted in healthy volunteers and in adult and pediatric patients with epilepsy. In healthy elderly (≥65 years) and younger adult (18–40 years) volunteers, the time to reach peak plasma concentration after drug administration (T_max) for MDZ following administration of MDZ-NS 2.5 or 5 mg was similar in both age groups (14.5–17.3 minutes) [53]. Exposure to MDZ (peak plasma drug concentration [C_max] and area under the plasma concentration–time curve from time zero to infinity [AUC_0–∞]) increased proportionally to dose and was higher in older versus younger participants (C_max 2.5/5 mg, 27.1/55.8 ng/mL vs. 22.5/46.1 ng/mL, respectively; AUC_0–∞ 2.5/5 mg, 70.0/157 ng·h/mL vs. 54.0/110 ng·h/mL, respectively) [53]. Elimination half-life (T_½) was longer in older participants (approximately 8 hours vs. approximately 6 hours in younger participants) [48,53]. However, the observation that PD effects (sedation and psychomotor impairment) of MDZ-NS were not significantly different between elderly and younger adults (see section 3.2) suggests that the differences in PK between the age groups may not result in clinically relevant changes in PD.

In adults with epilepsy, the T_max for MDZ-NS 10–20 mg was 9.0–19.0 minutes after single-dose administration and 19.0–21.5 minutes after repeat-dose administration [48]. Results in healthy adults and from a population PK analysis showed that MDZ plasma exposures increased approximately proportionally with dose up to 15 mg, but above this dose there was little to no increase in exposures [48]. T_½ ranged from 3.7–4.7 hours, shorter than that in healthy volunteers [48,53]. One reason could be the use of enzyme-inducing AEDs in patients with epilepsy. However, although exposures to MDZ and its metabolite 1-hydroxy midazolam (1-OH-MDZ) are reduced when cytochrome P450 3A (CYP3A) inducers are co-administered with MDZ-NS, the reductions are not expected to be clinically significant, as stated in the US label for MDZ-NS [44]. Furthermore, PD effects were similar between healthy participants and patients with epilepsy (see section 3.2), suggesting that the shorter T_½ may not be clinically relevant.

The PK of single-dose MDZ-NS 1.25, 2.5, or 5 mg was evaluated in pediatric (2–13 years) patients with focal or generalized epilepsy, with dose assigned by body weight [59,60]. The T_max for MDZ was 15 minutes for all cohorts. MDZ exposure (AUC_0–6) was lower in the 1.25- and 2.5-mg cohorts compared with the 5-mg cohort (37.2/38.4 ng·h/mL vs. 75.2 ng·h/mL), while there were no dose-dependent differences in C_max (33.7, 35.1, and 37.3 ng/mL in the 1.25-, 2.5-, and 5-mg cohorts, respectively).

MDZ is mainly metabolized by CYP3A4 to 1-OH-MDZ, which appears to be at least as potent as MDZ and may add to MDZ pharmacologic activity [44]. In adults with epilepsy, following MDZ-NS 10–20 mg administered as a single dose or as two doses given 10 minutes apart, 1-OH-MDZ plasma exposures (C_max and AUC) did not increase appreciably with dose [48]. Likewise, in pediatric patients 1-OH-MDZ plasma exposures did not vary across cohorts receiving MDZ-NS 1.25–5 mg [59].

It is important to note that the 1-OH-MDZ to MDZ ratios for MDZ-NS are lower than for oral MDZ (AUC_0-∞ 0.2 vs. 0.4; C_max 0.1 vs. 0.4 at 5 mg), which shows that intranasal administration avoids first-pass metabolism [48], and that the major site of MDZ absorption is in the nasal cavity, with minimal absorption via non-nasal routes (i.e. orally) [48]. Due to minimal first-pass metabolism, and absent functionally relevant genetic polymorphisms of CYP3A4/3A5 [61], the response to MDZ is predictable. Inter- and intra-participant variability in MDZ exposure (% coefficient of variation for C_max and AUC_0-∞) was low to moderate in healthy adults (inter- and intra-participant variability of 16–22% and 33–38%, respectively) [48].

In addition, because there is minimal first-pass metabolism, the potential for interaction with CYP3A4 inhibitors is expected to be similar to that of IV MDZ and reduced compared with oral MDZ [62]. As co-administration of CYP3A4 inhibitors with MDZ-NS could reduce plasma clearance of MDZ and lead to prolonged sedation, the US Prescribing Information for MDZ-NS states that concomitant use of MDZ-NS with moderate or strong CYP3A4 inhibitors should be avoided and that MDZ-NS should be used with caution when given concomitantly with mild CYP3A4 inhibitors [44].

3.5. Comparison with other MDZ formulations

A comparison of the PK of MDZ-NS, buccal MDZ, and intramuscular MDZ is shown in Table 1. The MDZ-NS PK parameters listed in the table are from the US Prescribing Information [44]. Peak absorption of MDZ is reached slightly faster with a 5-mg dose of MDZ-NS than with buccal MDZ or a 10-mg dose of intramuscular MDZ. C_max and AUC_0–∞ are both lower with MDZ-NS than with the other MDZ formulations. Bioavailability is also lower with MDZ-NS. T_½ is largely in the same range among the different MDZ formulations.

4. Clinical efficacy and safety

4.1. Phase I trials: safety and tolerability

A phase I, randomized, double-blind, placebo-controlled, dose-escalation trial evaluated PK, PD, safety, and tolerability of single- and repeat-dose regimens of MDZ-NS in adult (18–65 years; n = 60) patients with epilepsy on stable AED regimens (data on file). Patients received MDZ-NS 10, 15, 17.5, or 20 mg, or matching placebo as a single dose or repeat dose (total dose divided into two doses given 10 minutes apart).

MDZ-NS at doses up to 20 mg was generally safe and well tolerated following single- or repeat-dose administration. There were no deaths, unexpected treatment-emergent adverse events (TEAEs), serious TEAEs, or discontinuation of trial drug due to TEAEs (Table 2). Nearly all patients treated with MDZ-NS (97.9%) and patients randomized to placebo (83.3%) experienced TEAEs, which were all mild in intensity; no dose relationship of the incidence of TEAEs was identified.

TEAEs were mainly associated with the route of administration; TEAEs in the respiratory, thoracic, and mediastinal disorder System Organ Classes, specifically nasal discomfort and throat irritation, were reported in the majority of MDZ-NS patients (96%) and most were considered related to trial drug. There were no TEAEs related to respiratory or cardiorespiratory effects and oxygen saturation measurements <90% were not observed in any of the patients.

Since age may have important clinical effects on the PK of IV MDZ [63] and thus tolerability, the PK of MDZ-NS 2.5 mg or 5 mg was investigated in a phase I, randomized, double-blind, two-way crossover trial in elderly (≥65 years; n = 18) and younger adult (18–40 years; n = 12) volunteers to determine its potential for use in elderly patients [53] (see section 3.3). The differences observed between the age groups were considered to reflect a decrease in clearance in the older participants as opposed to an increase in bioavailability. Importantly, the extent of the increased exposure was not found to adversely affect tolerability. Overall, a similar percentage of elderly (89%) and younger (83%) participants had at least one TEAE, although a higher proportion of older participants reported at least one TEAE at the individual doses (Table 2). Most TEAEs were related to the nose, throat, and to taste [53].

An open-label, phase I trial in pediatric (2–13 years; n = 36) patients with epilepsy also showed that MDZ-NS was well tolerated [60,64]. Overall, 69.4% of patients had at least one TEAE; TEAE incidence was similar across dosing cohorts (5, 2.5, and 1.25 mg; Table 2). Most TEAEs (82.8%) were mild. TEAEs reported by >10% of patients were somnolence (58.3%) and product taste abnormal (11.1%). No treatment-related serious adverse events were reported, and there were no clinically meaningful effects attributed to MDZ-NS for clinical laboratory values, vital signs, or nasal examination results. One participant had a suicidal ideation assessment (Columbia Suicide Severity Rating Scale) of a wish to be dead during the past 6 months at the screening visit; no participants had any suicidal ideation or behavior at any time point during the trial [64].

4.2. Phase III trials: efficacy and safety

The efficacy and safety of MDZ-NS 5 mg in treating patients experiencing SCs were evaluated in the randomized controlled trial ARTEMIS-1 [54] and in its open-label extension ARTEMIS-2 [56]. In both trials, a SC was defined as an episode of at least two seizures (focal or generalized) that lasted at least 10 minutes and had an observable, stereotyped, and recognizably different pattern from the patient’s non-cluster seizure activity, with another seizure occurring within 6 hours of cluster onset. The randomized controlled trial recruited outpatients 12 years of age and older who were on a stable regimen of AEDs [54]. In total, 262 patients were randomized and 201 received double‐blind treatment for an SC, administered by a caregiver (MDZ-NS 5 mg n = 134, placebo n = 67). If the SC did not terminate within 10 minutes, or if another seizure occurred up to 6 hours after administration of the double-blind dose, an optional, open‐label 5-mg MDZ-NS dose could be given. The second dose was taken by 43 (32.1%) patients in the MDZ-NS group and 41 (61.2%) patients in the placebo group.

The trial demonstrated that MDZ-NS was superior to placebo in terminating seizure activity and in the probability of no further seizures over 24 hours, and was associated with a favorable safety profile [54]. Efficacy was measured using treatment success, defined as seizure termination within 10 minutes of, and no recurrence 10 minutes to 6 hours after, initial trial drug administration. Treatment success was significantly higher in the MDZ-NS group than in the placebo group (53.7% vs. 34.3%; p = 0.0109; Table 2). For the components of treatment success, 80.6% in the MDZ-NS group and 70.1% in the placebo group attained seizure termination within 10 minutes of trial drug administration, and 58.2% and 37.3%, respectively, did not experience further seizures at 10 minutes to 6 hours post dose [54]. Additionally, seizure recurrence from 10 minutes to 4 hours after trial drug administration was significantly lower in the MDZ-NS group compared with the placebo group (38.1% vs. 59.7%; p = 0.0043) [54].

Kaplan–Meier estimates of time to next seizure showed early separation (within 30 minutes) between MDZ-NS and placebo that was maintained throughout the 24‐hour observation period; the probability of experiencing no seizures over the observation period after 10 minutes of drug administration was significantly higher for MDZ-NS versus placebo (58.3% vs. 37.1%; p = 0.0124) [54].

Following administration of the double-blind drug in the outpatient comparative phase, 27.6% of patients in the MDZ-NS group and 22.4% in the placebo group experienced TEAEs, which were mostly mild or moderate in intensity [54]. Among the patients who received the open-label MDZ-NS dose, the incidence of TEAEs was 30.2% in the MDZ-NS group (MDZ-NS + MDZ-NS) and 22.0% in the placebo group (placebo + MDZ-NS) (Table 2).

In the MDZ-NS group, TEAEs that were most commonly reported within 2 days after trial drug administration (≥5% of patients who received the double-blind dose only or who also received the open-label dose) were nasal discomfort (double-blind dose only 5.5%, both doses 16.3%), somnolence (double-blind dose only 9.9%, both doses 9.3%), throat irritation (double-blind dose only 2.2%, both doses 7.0%), and headache (double-blind dose only 6.6%, both doses 2.3%) [54]. Treatment‐related TEAEs were reported by 22.0% of patients in the MDZ-NS group who received the double‐blind dose only, and 30.2% of those who received both doses; corresponding proportions in the placebo group were 19.2% (double-blind, placebo only) and 17.1% (double-blind placebo + open-label MDZ-NS).

Patients who completed the randomized controlled trial could have been enrolled into the open‐label extension ARTEMIS-2 (n = 175) [56]. During the time spent by patients in the ARTEMIS-2 trial (median 16.8 months), the majority of patients (92.0%) received at least one MDZ‐NS dose, for a total of 1998 SC episodes. As in the randomized controlled trial, in ARTEMIS-2 a second 5-mg dose of MDZ-NS could be administered if an SC episode did not terminate within 10 minutes, or if another seizure occurred 10 minutes to 6 hours after administration of the first 5-mg dose. In total, 109 patients received a second MDZ‐NS dose for 797 of 1998 episodes (39.9%).

In the outpatient setting, intermittent treatment with MDZ‐NS was well tolerated over an extended period, with maintenance of efficacy (Table 2). Treatment success was attained in 55.5% (95% confidence interval 53.2–57.7%) of SC episodes with the first dose and 80.2% (77.2–83.0%) with the second dose [56].

5. Post-marketing surveillance

Since MDZ-NS has only recently been approved for use to treat SCs, no post-marketing surveillance data are currently available. However, there are large video-EEG monitoring studies on the use of other intranasal MDZ formulations, which showed that the drug was well tolerated, with no major adverse events [65,66]. It is important to note that unlike MDZ-NS, the concentrated intranasal MDZ formulations used in the above-mentioned studies have an acidic pH, which leads to nasal irritations that not only cause discomfort, but may also make absorption less reliable [65–67].

6. Regulatory affairs

The FDA approved MDZ-NS, NAYZILAM® (MDZ) nasal spray, C-IV, on 17 May 2019 [68,69]. NAYZILAM® is marketed by UCB Pharma and there is currently no licensing filed to the European Medicines Agency for Europe. MDZ-NS is indicated for 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 who are 12 years of age and older [44]. MDZ-NS is the first FDA-approved nasal option for treating SCs [68]. In the US, it is the first new medication in over 20 years to be approved to treat SCs. It offers the benefits of intranasal administration, which allows for outpatient treatment by caregivers and other non-healthcare professionals, and may particularly be meaningful to patients who have limited treatment options [68]: for example, hypersalivation, jerking movements of the jaw, or general restlessness may rule out buccal administration of clonazepam and MDZ, and rectal diazepam may not be suitable because of the physical and social constraints to rectal administration [35].

7. Conclusion

For patients with epilepsy who experience SCs, effective antiseizure therapies that have few adverse effects, act rapidly, and can be easily administered by a caregiver, are needed. MDZ-NS is a new, intranasal formulation of MDZ optimized for single-dose delivery, and has been developed as a combination product along with the delivery device. MDZ-NS is rapidly absorbed in adults with epilepsy (T_max = 9.0–19.0 minutes following a single dose; 19.0–21.5 minutes after repeat-dose administration). Peak sedation effects of MDZ-NS (as assessed by SSS and OAA/S) occurred within 15–120 minutes in healthy adults, adults with epilepsy, and adolescents and adults with epilepsy and a history of SCs. In patients (12 years of age and older) experiencing SCs, the median time to return to baseline functionality was 72–92 minutes after MDZ-NS administration. Peak psychomotor impairment (as assessed by WAIS-IV) was observed at 20 minutes after MDZ-NS administration in adults with epilepsy and scores returned to baseline levels within 240 minutes post dose. No dose-dependent increases in sedation or psychomotor impairment were observed with MDZ-NS in patients with epilepsy.

The results from phase III clinical trials showed that MDZ-NS was superior to placebo in terminating seizure activity and in the probability of no further seizures over 24 hours. MDZ-NS was well tolerated in adult and pediatric patients with epilepsy during phase I and phase III trials. The ARTEMIS-1 and ARTEMIS-2 clinical trials provided evidence that MDZ-NS is a viable solution to treat SCs.

8. Expert opinion

MDZ is a well-established drug and is familiar to physicians. In the past, it was often administered by emergency personnel as an intramuscular dose (typically 10 mg) [70]. Before having an FDA-approved nasal product, the IV formulation was administered nasally using an atomization device [31]. Unfortunately, with this method the high volume (2 mL) meant that 80% or more was swallowed (each nostril can only hold 150–200 µL of administered drug [49]), resulting in decreased bioavailability; and the acidic pH [71] was very irritating to the nasal mucosa, limiting the use of this method. Another method of delivering MDZ intranasally is via concentrated MDZ nasal sprays, which reduces the volume administered to 140–840 µL [65,66]; however, these formulations also have a low pH and are associated with nasal irritation [65–67].

Now there is an MDZ-NS that can be easily administered by family members, using a portable nasal spray device. MDZ-NS works quickly and is effective (section 4.2), and has a quick return to baseline for sedation and psychomotor impairment (within 240 minutes post dose). This formulation of MDZ will be widely embraced by neurologists who until now had essentially no practical options to treat patients with SCs. Outside the US where MDZ-NS is not available, the alternative intranasal MDZ formulations described above may be important for patient treatment.

It is known that some patients with SCs progress to SE [2,4–6], but it is not possible to predict which ones will progress. Therefore, the best strategy for preventing this progression is to have a product such as MDZ-NS that interrupts SCs and to use it widely.

Limitations of MDZ-NS include its indication for patients 12 years of age and older, as no data are available in younger patients, and potential drug interactions with other benzodiazepines such as clobazam, which is frequently used in patients with SCs [72].

In the future, it would be advantageous to obtain data on the efficacy and safety of administering MDZ-NS for SCs in patients who have clobazam as one of their standard AEDs, and to generate data on the temperature stability of the nasal spray, to determine whether the formulation is stable over a wide range of temperatures or if it needs to be maintained at controlled room temperature (68–77°F or 20–25°C) [44].

This author believes that in the future, there will be multiple benzodiazepine products available, using differing routes of administration, so that the neurologist can individualize the treatment for SCs to that patient, taking into account their seizure type, seizure etiology, other medications, and potential for drug interactions, age, and the nature of their SCs. This will allow the patient to receive the best therapy for their SCs. At each follow-up visit, this should be reviewed to see if any adjustments in therapy are needed.

9. Information resources

‘Prolonged epileptic seizures: identification and rescue treatment strategies’, a supplement published in the educational journal of the International League Against Epilepsy that summarizes an international experts workshop on prolonged epileptic seizures [73]

Clinical resources page of the American Epilepsy Society website [74]

Epilepsy information page of the National Institute of Neurological Disorders and Stroke website [75].

Article highlights

• For patients with epilepsy who experience seizure clusters (SCs), effective antiseizure rescue therapies that have few adverse effects, act rapidly, and can be easily administered by a caregiver are needed.

• Midazolam nasal spray (MDZ-NS) is a new, intranasal formulation of midazolam that has been developed for outpatient treatment of patients experiencing SCs.

• MDZ-NS is rapidly absorbed in adults with epilepsy (T_max = 9.0–19.0 minutes following a single dose; 19.0–21.5 minutes after repeat-dose administration).

• Sedation and psychomotor impairment following MDZ-NS administration were rapid and transient, peaking within 15–120 minutes post dose and returning to baseline alertness and functionality within 240 minutes post dose; the effects were not dependent on dose in patients with epilepsy.

• Phase III trials showed that MDZ-NS was superior to placebo in terminating seizure activity and in the probability of no further seizures over 24 hours.

• Treatment success was consistent when a second MDZ-NS dose was used to treat an SC episode.

• MDZ-NS administration was well tolerated in adult and pediatric patients with epilepsy during phase I and phase III trials.

Declaration of interest

JW Wheless has received research grants from Aquestive, Eisai, Greenwich, INSYS Inc., LivaNova, Mallinckrodt, Neuralis, NeuroPace, Shainberg Foundation, and Zogenix; served as a consultant for Aquestive, BioMarin, Eisai, Greenwich, Mallinckrodt, Neuralis, NeuroPace, Shire, Supernus, and West; and participated in speaker’s bureau for BioMarin, Eisai, Greenwich, LivaNova, Mallinckrodt, and Supernus. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The author acknowledges and thanks the patients and volunteers participating in these trials. The author acknowledges Fabien Debailleul, PhD (UCB Pharma, Brussels, Belgium) for managing the development of the manuscript and Emily Chu, PhD (Evidence Scientific Solutions, London, UK) and Richard Fay, PhD, CMPP (Evidence Scientific Solutions, Philadelphia, PA, USA) for medical writing assistance, which was funded by UCB Pharma. The trials described in this manuscript were funded by Upsher-Smith Laboratories Inc. or Proximagen LLC.

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.

Additional information

Funding

This paper was supported by UCB Pharma.