Diazepam nasal spray (Valtoco; NRL-1), an investigational rescue medicine for epilepsy patients with seizure clusters or acute repetitive seizures, had high bioavailability and was tolerated well, researchers reported here.
Intranasal administration led to good diazepam exposure in patients on stable regimens of antiepileptic drugs who needed help controlling bouts of increased seizure activity, reported R. Edward Hogan, MD, of Washington University in St. Louis, at the American Epilepsy Society annual meeting.
The pharmacokinetic profile of intranasal diazepam was generally comparable to rectal administration but with less interpatient variability, he added.
“Intranasal delivery is attractive because it’s relatively easy, especially in an outpatient setting,” Hogan told MedPage Today. “The acute treatment form of diazepam that’s available right now is rectally administered [Diastat], which is not an ideal solution.”
From 25% to 50% of all epilepsy patients experience seizure clusters that are different than their baseline seizure pattern, noted Prakash Kotagal, MD, of the Cleveland Clinic Epilepsy Center, who wasn’t involved with the research.
“Seizure clusters may progress to status epilepticus and are associated with increased risk of morbidity and mortality and greatly impact quality of life,” he told MedPage Today. “Prompt treatment of seizure clusters is therefore imperative.”
Rectal administration of rescue medications is inconvenient, difficult, and not usually preferred by adults and older children, Kotagal noted. “Oral, buccal, or sublingual administration of benzodiazepines takes significantly longer to begin working,” he added. “Availability of intranasal benzodiazepines represents a significant step forward in making effective rescue medication for seizure clusters available for those in whom rectal administration is impractical.”
The researchers studied epilepsy patients during both ictal/peri-ictal (seizure) and inter-ictal (non-seizure) periods. Patients received open-label intranasal diazepam with at least 14 days washout between periods; either ictal/peri-ictal or inter-ictal administration could be first. In both periods, a single dose of 5, 10, 15, or 20 mg — depending on patient’s weight — was given. A second dose was allowed if seizures persisted.
In total, 57 patients received one or more doses and were included in the safety population, which was 54% female and 81% white. Both children and adults were studied; ages ranged from 6 to 59 and were an average of 28. Pharmacokinetic data were available from 49 patients through the 6-hour sampling period.
“At the end of the day, what we found was that dose concentrations in both situations — both the ictal/peri-ictal and inter-ictal periods — were very similar,” Hogan said.
Overall, median time to maximum plasma concentration was about 2 hours. Maximum plasma concentration and exposure over the first 6 hours were similar under both ictal/peri-ictal and inter-ictal conditions. Interpatient variability ranged from 53.6% to 59.3%, consistent with previous reports that showed the intranasal drug had less variability than rectal diazepam, Hogan said.
“Overall, this was a pretty well tolerated medication,” he added. “We saw nothing we wouldn’t expect to see with diazepam.” Seventeen patients (29.8%) reported treatment-emergent adverse events, most commonly dysgeusia (5.3%), nasal discomfort (3.5%), nasopharyngitis (3.5%), and seizures (3.5%). One patient experienced two serious adverse events — recurrent seizures and static encephalopathy — which were deemed not to be related to the treatment. There were no post-dose reports of suicide ideation.
Earlier this year, the FDA approved midazolam nasal spray (Nayzilam) as the first inhaled rescue medication for seizure clusters. Diazepam nasal spray is currently before the FDA; if it wins approval, it will be the third drug that works as rescue medicine for epilepsy patients to use during seizures on the market.
The study was supported by Neurelis.
Hogan disclosed support from UCB Pharmaceuticals, Neurelis, Biogen, and Engage Therapeutics.
EpilepsyU Source: MedPageToday.com by J. George
Primary Source: American Epilepsy Society
Source Reference: Hogan RE, et al “Pharmacokinetics and Safety of Valtoco (NRL-1; diazepam nasal spray) in Patients With Epilepsy During Seizure (Ictal/Peri-ictal) and Non-seizure (Inter-ictal) Conditions” AES 2019; Poster 2.122.