Efficacy, Tolerability, and Safety of Concentrated Intranasal Midazolam Spray as Emergency Medication in Epilepsy Patients During Video-EEG Monitoring

Abstract

Background An efficient, well tolerated, and safe emergency treatment with a rapid onset of action is needed to prevent seizure clusters and to terminate prolonged seizures and status epilepticus. Objectives This study aimed to examine the efficacy, tolerability, and safety of intranasal midazolam (in-MDZ) spray in clinical practice. Methods In this retrospective, multicenter observational study, we evaluated all patients with peri-ictal application of in-MDZ during video-EEG monitoring at the epilepsy centers in Frankfurt and Marburg between 2014 and 2017. For every patient, we analyzed the recurrence of any seizure or generalized tonic-clonic seizures after index seizures with and without in-MDZ administration. Treatment-emergent adverse events (TEAEs) were also evaluated. Results In-MDZ was used in 243 patients with epilepsy (mean age 35.5 years; range 5-76 years; 46.5% female) for treatment of 459 seizures. A median dose of in-MDZ 5 mg (i.e., two puffs; range 2.5-15 mg) was administered within a median time from EEG seizure onset until in-MDZ application of 1.18 min [interquartile range (IQR) 1.27], while median time from clinical seizure onset until in-MDZ administration was 1.08 min (IQR 1.19). In-MDZ was given within 1 min after EEG seizure onset in 171 seizures. An intraindividual comparison of seizures with and without application of in-MDZ was feasible in 171 patients, demonstrating that in-MDZ reduced the occurrence of any (Cox proportional-hazard model p < 0.001) and generalized tonic-clonic seizure (Cox proportional-hazard model p = 0.0167) over a period of 24 h. The seizure-free timespan was doubled from a median of 5.0 h in controls to a median of 10.67 h after in-MDZ administration. We additionally clustered in-MDZ administrations for the 119 patients who received in-MDZ more than once, comparing them with the index cases without in-MDZ. Even when considering subsequent seizures with in-MDZ administration, a patient receiving in-MDZ is still half as likely to incur another seizure in the upcoming 24 h as compared with when the same patient does not receive in-MDZ (hazard ratio 0.50; 95% CI 0.42-0.60; p < 0.01). In-MDZ was well tolerated without major adverse events. The most common side effects were irritation of the nasal mucosa [37 cases (8.1%)], prolonged sedation [26 cases (5.7%)], and nausea and vomiting [12 cases (2.6%)]. A decline in oxygen saturation was measured after 78 seizures (17%). Conclusion We conclude that in-MDZ is a safe and efficient treatment option to prevent short-term recurrence of seizures. In-MDZ can be administered very quickly by trained staff within 1-2 min after seizure onset. No major cardiocirculatory or respiratory adverse events were observed.

The Nose Knows: Intranasal Midazolam To Treat Acute Seizures During Inpatient Epilepsy Monitoring

“… 8 , 9 These 2 new products will be valuable options for patients during seizure clusters. The present study 3 is important because the inpatient location not only permitted corroboration of the effectiveness of in-MDZ reported in earlier studies but also provided accurate data both on the duration of effectiveness and on the length of post-dose sedation.…”

“…In the highlighted article, von Blomberg et al 3 report a retrospective study of 243 children and adults aged 5 to 76 (mean 35.5) years who had a total of 459 seizures. They describe the use of intranasal midazolam (in-MDZ) to abort seizures and control seizure frequency during inpatient video-electroencephalography monitoring (VEEG).…”

Time Is Brain: Acute Control of Repetitive Seizures and Status Epilepticus Using Alternative Routes of Administration of Benzodiazepines

“…The serum half-life of diazepam is longer than that of lorazepam, midazolam and clobazam, but both midazolam and diazepam have short CNS half-lives due to their higher lipophilicity. Lorazepam and clobazam have lower lipophilicity, and lorazepam has an onset of action of 3-5 min as compared to diazepam and midazolam, which cross the blood-brain barrier faster (e.g., 1-2 min) [47,50,51]. Due to this high lipophilicity, diazepam and midazolam also quickly redistribute out of the brain and only allow for short (e.g., <30 min) durations of seizure control when given intermittently.…”

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

“…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][66][67].…”

“…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][66][67].…”