A Phase 3 open-label study of the efficacy, safety and pharmacokinetics of buccally administered midazolam hydrochloride for the treatment of status epilepticus in pediatric Japanese subjects.

BACKGROUND

In Japan, intravenous (IV) administration of antiepileptic drugs in a healthcare setting is the preferred treatment option that is both licensed and recommended for initial treatment of status epilepticus (SE). However, prompt conveyance to a healthcare institution and IV access may be difficult in patients experiencing a seizure and so delay treatment. Thus, there is an unmet need for an alternative effective antiepileptic drug with an easier and more rapid mode of administration. In this study we evaluated a midazolam hydrochloride oromucosal solution (MHOS) that can be simply and rapidly administered to patients in SE.

METHODS

A Phase 3, interventional, multicenter, nonrandomized study was conducted in 28 clinical centers in Japan. Pediatric subjects in convulsive SE received treatment with buccal MHOS with dosage based on their age. The primary efficacy outcome was the percentage of subjects with seizure termination within 10 min and a 30-min absence of visible seizure activity from time of administration. Safety evaluations included respiratory depression and the frequency of treatment-emergent adverse events (TEAEs). Pharmacokinetic (PK) profile was also assessed.

RESULTS

The study population comprised 25 subjects with a median age of 2.8 years and median bodyweight of 13.4 kg. The primary efficacy outcome was achieved in 80 % of subjects; 84 % of subjects had seizure resolution within 10 min. Nine subjects experienced a total of 13 TEAEs, and protocol-defined respiratory depression occurred in one subject. Mean maximum plasma midazolam concentration was 78.0 ng/mL, and mean time to peak concentration was 20.5 min, demonstrating that achieving maximum plasma midazolam concentration is not required for seizure cessation.

CONCLUSIONS

The efficacy, safety and pharmacokinetic profile of MHOS in pediatric Japanese subjects was consistent with that observed in non-Japanese populations. Compared to IV treatments, MHOS offers easier administration which may reduce the time to treatment and thereby minimize the sequelae of prolonged seizures.