Safety of Diazepam Nasal Spray for Seizure Clusters in Patients Taking Maintenance Benzodiazepines

May 2022

For some patients with epilepsy, episodes of frequent seizure activity may still occur even when on maintenance antiseizure therapy. These seizure clusters are treated acutely with benzodiazepines. In 2020, the US Food and Drug Administration approved 2 benzodiazepine nasal sprays, diazepam and midazolam, for acute management of cluster seizures. Nasal sprays are more acceptable to patients and easier to deliver than rectally administered versions of the benzodiazepines, which have been used for decades.

Benzodiazepines can cause cardiorespiratory suppression and sedation. It is unclear whether an additional benzodiazepine dose in the form of a nasal spray for seizure clusters will increase the risk of adverse events in patients taking maintenance benzodiazepines. To determine the safety profile and effectiveness of diazepam nasal spray in patients taking concomitant maintenance benzodiazepines, the investigators conducted a phase 3 open-label clinical trial, which was published in Epilepsia.

The study included participants aged 6 to 65 years who had received a diagnosis of partial or generalized epilepsy. All had seizure clusters despite antiseizure therapies. They were divided into 3 groups based on concomitant benzodiazepine use: none, intermittent, or chronic. Participants were given diazepam nasal spray to be used as needed up to twice within 12 hours for acute treatment of seizure clusters with at least 5 days between treatments. The investigators analyzed safety for the subgroup that had used the diazepam during at least 1 year of follow-up.

A total of 158 patients used the diazepam nasal spray, and more than half used the nasal spray ≥2 times per month. As the investigators expected, patients who were not taking concomitant benzodiazepines used the nasal spray less often than did patients in the other groups, presumably because the use of concomitant benzodiazepines is related to epilepsy severity.

The use of a second dose during a single episode of seizure clusters was used by the investigators as a measure of the effectiveness of the nasal spray, and as such, no difference in the percentage of seizure clusters with second doses was seen between the chronic and no benzodiazepine groups (11.1% and 10.3%, respectively), indicating similar effectiveness.

More patients in the chronic benzodiazepine group had treatment-emergent adverse events compared with those not taking benzodiazepines (16.7% vs 10.3%, respectively). The investigators did not judge any of the serious treatment-emergent adverse events to be related to treatment. The investigators found it notable that no instances of cardiorespiratory suppression or sedation occurred. They pointed out, however, that the study excluded patients with cardiorespiratory conditions, so the safety results may be different for those with certain comorbidities.

“Taken together, these results show that diazepam nasal spray represents a potentially valuable treatment option for patients 6 years of age and older, irrespective of concomitant benzodiazepine use,” the investigators concluded.


Segal EB, Tarquinio D, Miller I, et al. Evaluation of diazepam nasal spray in patients with epilepsy concomitantly using maintenance benzodiazepines: an interim subgroup analysis from a phase 3, long-term, open-label safety study. Epilepsia. 2021;62(6):1442-1450.

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