Post-Dose Somnolence With Intranasal Midazolam Not Common, Study Finds

Kamil Detyniecki, MD

Results from a post hoc analysis of a phase 3 trial of intranasal midazolam (Nayzilam; UCB Pharma) in patients with seizure clusters (SC) showed a low incidence of post-dose somnolence. The findings were presented at the 73^rd annual meeting of the American Epilepsy Society, December 6-10, 2019, in Baltimore, Maryland.

Investigators examined data from the phase 3 ARTEMIS-1 trial (NCT01390220), which evaluated safety and efficacy of intranasal midazolam in patients aged ≥12 with SC. Patients were initially enrolled in an open-label test dose phase, and then were randomly assigned 2:1 to 5 mg midazolam or placebo; an optional, open-label 5 mg dose was available if the SC did not terminate within 10 minutes or if another seizure occurred within 6 hours of initial dose administration.

Investigators assessed patients on time to onset of somnolence, duration of somnolence, and return to baseline functionality within 24 hours of midazolam administration in patients

reporting versus not reporting somnolence. Return to baseline functionality was judged by the caregiver and was documented when the patient returned to what he/she was doing.

Ultimately, 292 patients received a test dose, and 201 were randomized to intranasal midazolam or placebo. Among those randomized, 175 received at least 1 dose of the study drug (n=91 midazolam 5 mg; n=43 midazolam 5 mg plus5 mg; n=41 placebo plus midazolam 5 mg) and 26 received placebo only. Overall, 10.6%, 9.7%, and 3.8% of patients in the test-dose phase, those who received >1 midazolam dose, and those in the placebo group experienced somnolence.

The median time to somnolence onset following administration of midazolam was 15 and 5 minutes in the test-dose and randomized phases, respectively. Patients in the test-dose phase experienced somnolence for an median of 1.14 hours compared to 4.13 hours in patients who received >1 dose of midazolam in the randomized phase.

Of the 158 patients in the randomized phase who did not report somnolence, 90 (57%) returned to baseline functionality within 24 hours of first midazolam dose, with a median time to return of 1.05 hours. Among the 17 patients who did report somnolence, 10 returned to baseline functionality within 24 hours, with an median return time of 1.54 hours.

Among patients in the randomized phase who received an additional open-label, 5 mg dose of midazolam, 20.5% and 25% of patients who did not experience somnolence compared with those who did experience somnolence, respectively, returned to baseline functionality. Additionally, 8.1% of patients who did not report somnolence after receiving placebo plus 5 mg of midazolam returned to baseline functionality within 24 hours.

The data suggest that the rate of return to full baseline functionality within 25 hours is affected more by the degree of SC control and the need for an additional dose of intranasal midazolam rather than somnolence.

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REFERENCE

Detniecki K, Campos R, Cleveland J, Kakhoury T, Greenaway L. Somnolence and time to return to baseline functionality after midazolam nasal spray delivery in patients with seizure clusters: posts hoc analysis of a randomized, double-blind, placebo-controlled trial. Presented at: 2019 American Epilepsy Society AnnualMeeting. December 6-10, 2019; Baltimore, Maryland. Abstract 2.243