FDA Approves Midazolam Nasal Spray for Seizure Clusters

Steven S Chung, MD, Executive Director and Program Chair of the Neuroscience Institute and Director of the Epilepsy Program at Banner University Medical Center

Steven Chung, MD

The FDA has approved a new drug application for midazolam (Nayzilam, UCB) nasal spray, a Schedule IV Controlled Substance, for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity that are distinct from usual seizure pattern in patients with epilepsy 12 years of age and older, according to UCB.

The benzodiazepine, which may be administered in the outpatient setting by a non-healthcare professional in patients actively seizing and where a seizure cluster occurs, is supplied as 2 single-use nasal spray units, each containing a 5 mg dose of midazolam in 0.1 mL solution. The prescribing information warns that concomitant use of benzodiazepines, including midazolam, and opioids may result in intense sedation, respiratory depression, coma, and death, and for patients at increased risk of respiratory depression, administration of midazolam under healthcare supervision should be considered prior to treatment.¹

The effectiveness of midazolam was established in a phase 3 randomized, double-blind, placebo-controlled trial (NCT01390220) that was conducted in 2 phases: an open-label test dose phase followed by a comparative phase.

“When a patient experiences seizure clusters, there is often significant impact on their overall quality of life, in addition to posing greater risks for increased emergency department related hospitalizations and more serious seizure emergencies,” Steven Chung, MD, executive director and program chair of the Neuroscience Institute and director of the epilepsy program, Banner - University Medical Center, said in a statement.² “Further, as a neurologist specializing in epilepsy, treating seizure clusters today presents a challenging barrier for many patients. The availability of a new treatment option, such as Nayzilam, has potential to help improve the lives of patients and their families by providing another option for rescue care.”

Phase 1 of the trial included patients with epilepsy on a stable regimen of antiepileptic drugs identified as having intermittent, stereotypic episodes of frequent seizure activity distinct from the patient's usual seizure pattern.

In the test dose phase, tolerability was assessed in 292 patients who, in the absence of a seizure, received 2, 5 mg doses of midazolam 10 minutes apart. Study participants that failed to meet pre-identified blood pressure, heart rate, sedation, electrocardiogram, and peripheral oxygen saturation criteria were excluded from participating in the comparative phase.

In the comparative phase, patients treated a single seizure cluster episode in an outpatient setting with either a blinded dose of midazolam 5 mg (n=134 patients) or placebo (n=67); if seizure activity recurred or persisted, patients in both groups had the option to receive a subsequent unblinded dose of midazolam 5 mg, which was used between 10 minutes and 6 hours after administration of the initial dose.

The primary efficacy endpoint of Study 1 was treatment success, defined as achieving both of the following: termination of seizure(s) within 10 minutes after study drug administration, and no recurrence of seizure(s) beginning 10 minutes after study drug administration to 6 hours after administration.

Investigators reported that a statistically significant higher percentage of patients treated with midazolam met the primary efficacy endpoint; termination of seizure(s) within 10 minutes after the initial dose of study drug (80.6% versus 70.1%) and the absence of seizure(s) recurrence between 10 minutes and 6 hours after the initial dose of midazolam (58.2% versus 37.3%).

Additionally, Study 1 also evaluated the occurrence and time to the next seizure after the initial blinded study dose and saw that a smaller proportion of midazolam-treated patients experienced the next seizure 24 hours after the initial dose of midazolam (37.3% versus 46.3%).

The most common adverse reactions ≥5% in any midazolam treatment group in the trial were somnolence, headache, nasal discomfort, throat irritation, and rhinorrhea.

REFERENCE

1. NAYZILAM [prescribing information]. Smyrna, Ga.: UCB; 2019. ucb-usa.com/_up/ucb_usa_com_kopie/documents/Nayzilam_PI.pdf. Accessed May 20, 2019.

2. UCB announces NAYZILAM® (midazolam) nasal spray now approved by FDA to treat intermittent, stereotypic episodes of frequent seizure activity in people living with epilepsy in the U.S. [news release]. Brussels, Belgium, Atlanta, Ga.: UCB; May 20, 2019. ucb.com/stories-media/Press-Releases/article/UCB-announces-NAYZILAM-midazolam-nasal-spray-now-approved-by-FDA-to-treat-intermittent-stereotypic-episodes-of-frequent-seizure-activity-in-people-living-with-epilepsy-in-the-U-S. Accessed May 20, 2019.