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Limited published evidence of safety

Long half-life of diazepam and its active metabolites increases risk of accumulation in breastfed infants

Adverse effects reported include sedation and poor feeding

Monitor the infant closely for drowsiness, poor feeding and adequate weight gain

Long half-life increases risk of accumulation in breastfed infants with repeated doses

Adverse effects reported include sedation and poor feeding

Short-term therapy (1-2 doses) considered not to pose a risk to the infant

Long half-life increases risk of accumulation in breastfed infants with repeated doses

Adverse effects reported include sedation and poor feeding after prolonged use

Short-term therapy (1-2 doses) considered not to pose a risk to the infant

Long half-life increases risk of accumulation in breastfed infants

Adverse effects reported include sedation and poor feeding

Sep 20 · Neurelis plans a clinical trial for epilepsy in children in the US and plans to file an sNDA to the FDA in 2021. The company does not currently appear to have plans to bring this product to EU/UK markets [6].

Mar 20 · Launched in US [5].

Jan 20 · Approved in US for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e. seizure clusters, acute repetitive seizures) that are distinct from a patient ´s usual seizure pattern in adult and pediatric patients six years of age and older [5].

Sep 18 · Filed in the US with Fast Track designation as a treatment for epilepsy patients six years and older who experience increased bouts of seizure activity, also known as cluster or acute repetitive seizures [1].

The prevalence of acute repetitive seizures (ARS) is not well known. A population-based study of ARS in the UK estimated that the crude prevalence in the general population was 2.3 per 10,000. The prevalence was highest in the very young (ages 0–4) at 5.9 per 10,000, and declined with age to 0.5 per 10,000 in those aged ≥70. They estimated that ARS affect about 3% of the epilepsy population. There is evidence that the prevalence of ARS in an epilepsy-centre population is much higher [2].

Oct 19 · Neurelis releases updated results from PIII trial (NCT02721069). Previously they presented safety data at the 71th Annual Meeting of the American Academy of Neurology (AAN-2019) [4].

Apr 16 · Pivotal PIII trial initiated to evaluate the safety of repeated doses of diazepam intranasal (NRL-1) in epilepsy subjects who have frequent breakthrough seizures or Acute Repetitive Seizures (ARS), to support US filing (NCT02721069). The open-label, 12-month, repeat-dose study estimates enrolment of 80 patients in the US [3].

US label

Nov 20 · After submitting a meeting package in October, the company announces that a review meeting with the FDA is set for November 12, 2020. The company does not believe additional studies are needed. At that Nov meeting, Aquestive will seek to confirm the pathway for approval and propose the immediate re-submission of the NDA for Libervant. If the FDA agrees with the proposal, then the Company plans on resubmitting the NDA before the end of the year. If the FDA does not agree, then the Company will seek to understand the best path forward for re-submission and approval [7].

Nov 20 · Diazepam buccal soluble film was awarded fast track status in US in Dec 18 [6].

Sep 20 · FDA issues a Complete Response for diazepam buccal film. In the letter, FDA cite that, in a study submitted with NDA, certain weight groups showed a lower drug exposure level than desired. Aquestive Therapeutics are asked to provide additional pharmacokinetic data to demonstrate that dose adjustments will obtain the desired exposure levels [5].

Nov 19 · Plans for EU development not discussed in company quarterly report [4].

Nov 19 · Aquestive Therapeutics intends to complete the rolling NDA submission by end of Nov 19, and launch in the US in 20 [3].

May 19 · Aquestive Therapeutics initiated a rolling new drug application (NDA) submission for diazepam buccal soluble film with the US FDA for the treatment of seizure [3].

Oct 18 · Has orphan drug status in US [2].

The prevalence of active epilepsy is 5-10 cases per 1,000 - but with 5-30% of these misdiagnosed as having epilepsy [1].

Jun 20 · PIII trial that evaluated the safety and tolerability of the buccal formulation of diazepam, patients aged two to 65 years, with epilepsy completes (42-1703; NCT03428360) [6].

Oct 18 · Pharmacokinetic epilepsy monitoring unit (EMU) study of diazepam buccal film demonstrates a comparable bioavailability when administered between seizures or during and shortly after seizures in adults with poorly controlled tonic-clonic seizures or focal seizures with impaired awareness [2].

Jan 18 · PIII trial to evaluate the safety and tolerability of the buccal formulation of diazepam, patients aged 2 to 65 years, with seizures starts (NCT03428360). The open label trial is intended to enrol 120 patients in the US [2].

Jul 17 · PII trial to evaluate the pharmacokinetics, tolerability and safety of diazepam buccal film for the treatment of patients with epilepsy starts (NCT03222349). 18 patients, aged 2 to 17 years, will be enrolled by invitation in the US [2].