Pharmacokinetics and 180-day safety of diazepam nasal spray in pediatric patients with epilepsy aged 2-5 years.

OBJECTIVE

Benzodiazepine immediate-use seizure medications (ISMs; also called rescue therapies) are used to treat seizure clusters/acute repetitive seizures in patients with epilepsy. In the United States, diazepam nasal spray is an approved ISM for patients ≥2 years of age. The primary objective was to assess diazepam nasal spray pharmacokinetics (PK) in patients 2-5 years of age; safety and tolerability were secondary objectives.

METHODS

This Phase 1/2a, open-label, single-dose, PK study with a 180-day open-label safety period enrolled patients with epilepsy 2-5 years of age. Diazepam nasal spray (0.5-mg/kg per diazepam rectal gel dosing) was administered by a medical professional, followed by PK sampling. During the safety period, caregivers administered diazepam nasal spray as needed for frequent or acute repetitive seizures. Seizures and dosing were recorded in a diary. Study visits included safety evaluations. Use of second doses was a proxy for effectiveness.

RESULTS

Thirty-six patients were enrolled, with 35 in the PK population. PK parameters and modeling were comparable to older children and adults, confirming that diazepam nasal spray was readily absorbed and supporting the adequacy of the 0.5-mg/kg dose for this age group. In the open-label period, second doses within 24 h of the initial dose were administered for 16.3% of seizure events (37/227), indicating that a second dose was not used for most seizure events (83.7%). Treatment-related treatment-emergent adverse events occurred in seven patients (19.4%); all were mild except one (moderate). There was one report each of respiratory depression and respiratory distress; neither was treatment related.

SIGNIFICANCE

This study characterizes the PK of diazepam in patients 2-5 years of age and reports a safety profile consistent with older patients. Results demonstrate that the diazepam nasal spray drug-device combination is appropriate for drug delivery and absorption in these patients.