Diazepam Buccal Film Comparable to Rectal Gel With Good Safety, Tolerability Profile

Keith J. Kendall

Chronic intermittent treatment with diazepam buccal film (Libervant; Aquestive) is safe and tolerable in patients with seizure clusters, with comparable bioavailability to rectal diazepam, according to study results presented at the 2019 American Epilepsy Society Annual Meeting, December 6-10, 2019, in Baltimore, Maryland.^1,2

Notably, Aquestive recently completed submission of its rolling NDA for Libervant to the FDA, from whom it was granted orphan drug designation.³ The FDA had previously requested that the company conduct a dose crossover study comparing the buccal film to the approved reference drug Diastat (Valeant), results of which were presented at the meeting.

“We believe that Libervant has the potential to be the first oral therapy approved by the FDA for the management of seizure clusters in the population of 1.2 million refractory epilepsy patients and the first diazepam-based treatment usable by and delivering a consistent predictable dose to virtually all patients to whom it will be prescribed,” Aquestive Therapeutics CEO Keith J. Kendall said in a statement.³

In the single-dose crossover study (NCT03953820),¹ adult patients age 18 to 65 with epilepsy who were on a stable regimen of ³1 antiepileptic drug were randomly assigned to receive a single dose of either diazepam buccal film or diazepam rectal gel separated by a 28-day washout period. Both drugs were administered according to a weight-based regimen (dose range: 12.5-17.5 mg for buccal film; 12.5-20 mg for rectal gel for 51-111 kg). Plasma concentrations of diazepam were collected pre-dose as well as at various intervals through 10 days post-dose to determine maximal plasma concentration (Cmax), time to Cmax (Tmax), area under the curve to last measurable concentration (AUC0-T) and AUC extrapolated to infinity.

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Overall, 31 patients were enrolled and 28 were included in the final analysis. Mean dose of diazepam buccal film and rectal gel was 15.4± -1.9 mg and 17.1± -3.0 mg, respectively. Mean Cmax values for buccal film were 204.26 ng/mL compared with 211.22 ng/mL in the rectal gel group, demonstrating comparable but less variable Cmax values with diazepam buccal film versus rectal gel (P <.0001). Across the different weight categories, mean Cmax values were consistently 150 ng/mL in the buccal film group. AUC values were greater for diazepam buccal film compared to rectal gel, and median Tmax values were 1.0 and 0.52 hour for buccal film versus rectal gel, respectively (P <.05). Notably, 3 patients assigned to diazepam rectal gel failed to achieve a Cmax of ³70 ng/mL; no serious adverse events (AEs) were recorded.

Results of an ongoing, phase 3, safety and tolerability trial (NCT03428360) were also presented.² Patients age 2 to 65 were included in the study and received diazepam buccal film doses ranging from 5 mg to 17.5 mg depending on age and weight. Doses were administered at home by the patient or a caregiver, and could be given for up to 5 seizure episodes per month. Safety and tolerability outcomes, including AEs and usability were recorded after the first dose and then every 3 months thereafter.

Results of this interim analyses included data from 72 patients (adults, n = 59; adolescents, n = 7; pediatric, n = 6). Overall, 6.9% (n = 5) of patients reported 7 mild treatment-related AEs over a mean of 192 days of follow-up, with 1 patient reporting mild local buccal discomfort. Thirteen serious, but non-treatment-related AEs were reported; however no patients discontinued participation due to AEs. The most common treatment-related AEs were somnolence, lethargy, altered state of consciousness, mouth swelling, oral discomfort, gait disturbance, and skin sensitization (all n = 1).

Among the study cohort, 64 patients reported usability outcomes, representing 471 diazepam buccal film use occasions (mean, 7.4 administrations per patient). Successful administration of the study drug on first attempt was achieved in 94.1% of use occasions, with another 3.6% on second attempt. Notably, all 64 patients achieved first-attempt success on at least 1 occasion. Among the 471 use occasions reported, reasons for unsuccessful administration included excessive drooling, jaw clenching, trouble opening the mouth, or the medication being spit out or swallowed prior to it adhering to the buccal mucosa.

Overall, the results demonstrate that diazepam buccal film may represent a safe and tolerable alternative to diazepam rectal gel with comparable bioavailability. The alternate route of administration may ultimately be a more accessible, usable, and socially acceptable formulation for both patients and caregivers.

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REFERENCES

1. Rogawski MA, Heller AH, Farrow S, et al. Pharmacokinetics of diazepam buccal film in adult patients with epilepsy: comparison with diazepam rectal gel. Presented at: 2019 American Epilepsy Society Annual Meeting. December 6-10, 2019; Baltimore, MD. Abstract 1.432.

2. Seinfeld S, Gelfand M, Heller AH, Buan C, Slatko G. Safety and tolerability associated with chronic intermittent use of diazepam buccal film in pediatric, adolescent, and adult patients with epilepsy. Presented at: 2019 American Epilepsy Society Annual Meeting. December 6-10, 2019; Baltimore, MD. Abstract 3.444.

3. Aquestive Therapeutics completes rolling submission of new drug application (nNDA) to US Food and Drug Administration (FDA) for Libervant™ (diazepam) buccal film for management of seizure clusters [news release]. Warren, NJ: Aquestive Therapeutics. December 2, 2019. aquestive.com/aquestive-therapeutics-completes-rolling-submission-of-new-drug-application-nda-to-u-s-food-and-drug-administration-fda-for-libervant-diazepam-buccal-film-for-management-of-seizure-clu/. Accessed December 11, 2019.