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.

Bioavailability and Safety of a New Highly Concentrated Midazolam Nasal Spray Compared to Buccal and Intravenous Midazolam Treatment in Chinese Healthy Volunteers

“…Most concentrated intranasal solutions have an acidic pH, which can cause nasal irritation, discomfort, and less reliable absorption of midazolam [9,14,35,36]. The solubility of MDZ was greatly increased by decreasing the pH from near-physiological values to pH 3.3.…”

“…Benzodiazepines (diazepam and midazolam) are the most commonly used, first-line drugs for the management of acute seizures [4,7,8]. Buccally administered midazolam (BC-MDZ) and rectally administered diazepam are recommended for treating seizure clusters in several authoritative guidelines in China, and they are licensed in the European Union [9,10]. As a result of the disadvantage of inconvenient use of the rectal preparation [10] and the buccal route of administration often being hampered by jaw clenching, hypersalivation, or uncontrolled swallowing [11], which limits their use in the acute setting [12], a nasal spray was developed for both drugs and approved by the US Food and Drug Administration (FDA) in 2019 and 2020, respectively [9].…”

“…Buccally administered midazolam (BC-MDZ) and rectally administered diazepam are recommended for treating seizure clusters in several authoritative guidelines in China, and they are licensed in the European Union [9,10]. As a result of the disadvantage of inconvenient use of the rectal preparation [10] and the buccal route of administration often being hampered by jaw clenching, hypersalivation, or uncontrolled swallowing [11], which limits their use in the acute setting [12], a nasal spray was developed for both drugs and approved by the US Food and Drug Administration (FDA) in 2019 and 2020, respectively [9]. The FDA reported that midazolam nasal spray presented improved bioavailability compared with intranasal delivery of midazolam formulation intended for intravenous delivery; however, there is a lack of randomized controlled trials (RCT) directly comparing the bioavailability of intranasally administered midazolam (IN-MDZ) with BC-MDZ [13].…”

The Evaluation of the Efficacy and Safety of Midazolam Nasal Spray in Patients With Seizure Clusters: A Systematic Review and Meta-Analysis

“…So, in such cases, the intranasal route is beneficial because it is painless, noninvasive, and easy to access [14,15]. But the intranasal route in nasal solution form is not standardized, and local irritation may occur because of the acidic solution (2.8-3.0 pH), and the small volume of the nasal cavity requires high doses, which leads to a significant first-pass effect and decreased bioavailability and efficacy [16][17][18]. So, the development of nasal spray formulation (midazolam nasal spray {MDZ-NS}) became a promising alternative in emergency cases as rescue medication where other routes are not feasible.…”

“…So, the development of nasal spray formulation (midazolam nasal spray {MDZ-NS}) became a promising alternative in emergency cases as rescue medication where other routes are not feasible. It is also observed that the metabolic compound of midazolam nasal spray (MDZ-NS) to MDZ ratio for MDZ-NS is lower than oral MDZ, demonstrating that intranasal administration avoids first-pass metabolism [16][17][18].…”