PHILADELPHIA—Intranasal delivery of diazepam is feasible for patients with seizure clusters or prolonged seizures, according to data presented at the 66th Annual Meeting of the American Academy of Neurology. Caregivers can administer the drug during or immediately after seizures. In addition, the drug appears to be well tolerated and may not be associated with any serious adverse events.
The average peak concentration of diazepam was approximately 200 ng/mL, said Michael R. Sperling, MD, Professor of Neurology and Director of Jefferson Comprehensive Epilepsy Center at Thomas Jefferson University in Philadelphia. Research published in the 1980s indicated that peak concentrations of rectal diazepam greater than 80 ng/mL had antiepileptic effects and that peak concentrations of approximately 150 or 200 ng/mL had therapeutic effects. Although the current study examined pharmacokinetics, and not efficacy, its results suggest that intranasal diazepam reaches levels that affect EEG and seizures, said Dr. Sperling.
Patients Were Treated in an Epilepsy Monitoring Unit
The only medicine to treat seizure clusters that has received FDA approval is rectal diazepam. Although the therapy is used widely around the world, researchers have been attempting in recent years to develop alternatives that are more socially acceptable. Dr. Sperling and colleagues conducted a pharmacokinetics study to determine the serum levels that intranasal diazepam attains. The investigators also examined the drug’s safety and tolerability.
A total of 78 patients admitted to an epilepsy monitoring unit were enrolled in the study. Eligible patients had a clear diagnosis of epilepsy, were between ages 18 and 65, and weighed between 50 and 111 kg. Patients who were allergic to diazepam or who had used diazepam within two weeks of study entry were excluded. After screening, the researchers excluded 10 of the 78 patients from the trial. Participants’ average age was 35, and average weight was 75 kg. More than half of the population was female.
Blood samples were collected at the beginning of the study. Of the remaining 68 participants, 31 had seizure clusters in the epilepsy monitoring unit and received 0.2 mg/kg of intranasal diazepam (ie, one 0.1-mL spray per nostril) instead of the unit’s usual rescue therapy. The investigators collected 10 additional blood samples at various intervals during the 12 hours following treatment. If patients had additional seizures after dosing, they were treated appropriately.
Drug Absorption Was Consistent
A total of 10 patients had tonic-clonic seizures and received intranasal diazepam during the seizures. Seven patients received the drug within five minutes of their seizures, and 13 patients received the drug more than five minutes after their seizures. One patient withdrew consent after dosing. Diazepam levels were measurable in the plasma within 10 minutes.
The average peak concentration of intranasal diazepam was 208 ng/mL. Peak concentration was 194 ng/mL during the tonic-clonic seizures, 220 ng/mL for patients who received treatment within five minutes of the seizure, and 213 ng/mL for patients who received treatment more than five minutes after the seizure. Average time to peak concentration was approximately an hour overall. “You’ve got very similar patterns of absorption and relatively good absorption in patients,” said Dr. Sperling.
Approximately two-thirds of participants were seizure-free during the 12 hours after dosing. “Again, this is not an efficacy study,” said Dr. Sperling. “You can’t draw any conclusion that [intranasal diazepam] works two-thirds of the time.” The average time to relapse seizure was about 4.8 hours, and the shortest time to relapse seizure was about 20 minutes. Additional rescue medication was required for three of the 30 patients.
Safety and tolerability were difficult to gauge in this study, continued Dr. Sperling. “You can’t distinguish between the effect of the seizure and the effect of the drug, although we can reasonably say that tongue injury … in four patients is from the seizure.” Adverse events included headache, dysgeusia, nasal discomfort, and increased lacrimation, but they all occurred in the postictal period.
Four patients had nasal discharge after dosing, but diazepam stayed in the nose, overall. The amount of leakage from the nose is probably less than the amount of leakage from the rectum, said Dr. Sperling. The investigators did not analyze the nasal leakage to determine whether it included diazepam, but they observed that patients with nasal secretions tended have lower peak concentrations of drug.