Diazepam Buccal Film’s Role in Treating Intermittent Pediatric Seizures, with Michael Rogawski, MD, PhD

Michael Rogawski, MD, PhD

The FDA has approved Aquestive Therapeutics’ diazepam buccal film, marketed as Libervant, for the treatment of pediatric patients with intermittent, stereotypic episodes of frequent seizure activity (seizure clusters, acute repetitive seizures). Indicated for those between 2 and 5 years of age, the therapy offers patients a compact, easily administered diazepam formulation.

Click here for Contemporary Pediatrics’ full coverage of the approval.

Benzodiazepines, including diazepam and midazolam, are the mainstay of treatment for seizure emergencies, including acute repetitive seizures. Prior to the approval of Libervant, diazepam rectal gel (Diastat) was the only treatment currently available to this patient population. Libervant, a buccal form of diazepam administered on the inside of the cheek, was also previously approved for patients 12 years of age and older in August 2022, but remains in an orphan drug block to market access until January 2027.

The approval was based on a crossover study that included 24 patients, aged 2-16 years old with refractory epilepsy, who received diazepam buccal film at doses of 5.0 to 17.5 mg in an epilepsy monitoring unit setting. Of these included, 17 were in the interictal period and 16 in the periictal period, with 9 subjects dosed in both periods. All told, diazepam least square mean maximum plasma concentrations were somewhat higher in the interictal state than in the periictal state, but these differences were not statistically significant.

Presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, investigators reported no difference in the median time to maximum diazepam concentration when patients were dosed in either seizure state. Overall, the study authors concluded that this formulation provides a more convenient way to deliver diazepam for the treatment of acute repetitive seizure emergencies in children.

For more insight on how the approval of diazepam buccal film may impact pediatric patients with intermittent seizure frequency, NeurologyLive® sat down with Michael Rogawski, MD, PhD, a distinguished professor of neurology and pharmacology at the University of California Davis Health Medical Center. Rogawski gave comment on the significance of having a new administration route for diazepam, what clinicians should be aware of with its use, and some of the major points of emphasis from its clinical program.

NeurologyLive: What is the significance of an approval like this?

Michael Rogawski, MD, PhD: It provides a new option to treat seizure emergencies. It is a new dosage form for administering diazepam, which is well-recognized as an efficacious treatment for acute seizure emergencies. When I refer to acute seizure emergencies, the indication the product is approved for, I’m referring to acute repetitive seizures, which is a synonym for seizure clusters, or sometimes referred to as seizure flurries. This is a condition where a patient has an increase in seizure frequency, and there is a concern on the part of a caregiver that this unusual seizure pattern could lead to additional seizures and potentially to status epilepticus, which is a life-threatening seizure emergency. The intent of products like this is to inhibit the occurrence of additional seizures and prevent the deterioration of the patient to status epilepticus.

How important is it to have multiple options of administration?

Up until recent, there was only one FDA-approved form of diazepam for clinical use in this indication, and that is rectal diazepam or Diastat. While this is a useful dosage form—in some cases, for example, in small children, it's a feasible route of administration—it's generally not preferred by caregivers, for obvious reasons. It can be embarrassing for the patient and the caregiver. It is a route of administration that is generally not feasible for larger patients and adults because of the difficulty of simply positioning an adult appropriately for rectal administration. Of course, there is also the embarrassment factor on the part of both the patient and the caregiver. In recent years, there have been approvals of newer dosage forms, but the diazepam buccal film product provides an entirely new way of administering diazepam that hasn't heretofore been available in the United States or actually anywhere in the world. This is a very innovative and new product concept, if you will.

Are there any safety concerns clinicians should be mindful of?

There's two things to say in regard to this question. Firstly, the clinical trials that were presented to the regulators during the approval process demonstrated that Libervant is able to very reliably delivered diazepam. In my view, the reliability exceeded that of other products that have been approved previously. The fluctuations in blood levels that were achieved with the legacy products is greater. From a safety perspective, which is the source of your question, it's important that we reliably deliver the diazepam product as intended.

In head to head testing in comparison with the rectal gel, as well as if you compare the results that have been reported in the literature vs the other legacy products, Libervant performed more consistently, and the blood levels that were achieved had a much tighter range of fluctuations than the other products. The product needs to get to the patient so that it can stop the seizure. By having a more consistent delivery, the product is ultimately safer because less patients will have subtherapeutic blood levels and not achieve not obtain enough medication. The second way to think about it is in terms of the safety of the dosage form. And to date, there haven't been any safety concerns there.

Diazepam buccal film is a very thin polymer film, a very small piece of film that contains diazepam, uniformly distributed throughout the film. The film has a mucoadhesive property, which means that it binds very tightly to the buccal mucosa inside the cheek. It very rarely will fall off if it's placed properly within the cheek. The evidence from the clinical trials indicated that it is easy to administer and that there weren't any issues related to problems with administration. It was always very reliably administered. When it is reliably administered, it sticks to the interior of the cheek, and it rapidly dissolves, delivering the diazepam across the buccal mucosa. Some of it is also swallowed. It's absorbed through the GI tract as well. Because it has this mucoadhesive property, it stays in place. That, I believe accounts for why it's able to deliver the diazepam so reliably. The film itself is inert and doesn't irritate the cheek, doesn't produce any untoward symptoms in the patients. It's been studied in children is as young as two years of age, and there haven't been any increased problems in the younger age groups than what was seen in clinical testing in adults.

From the clinical trial program of diazepam buccal film, what stands out?

I was involved in planning for all the clinical trials, the data analysis, and the reporting of the clinical trials since the inception of the program from the first subject. In all cases, I've been impressed with the usability of diazepam buccal film in all of the populations that the product has been studied, whether it's normal volunteers, people with epilepsy, adults and children with epilepsy. The product has high usability, and what I mean by that is that a caregiver can administer it quite easily and reliably. Also, patients can administer it themselves easily and reliably. The rectal product can’t be self administered. That's not possible. The nasal sprays can be self-administered, and Libervant is quite readily self-administered. If a patient feels that their seizure frequency is increased, and they're concerned about continuing to have seizures, they can reach for this product.

Diazepam buccal film is packaged in a thin foil pouch that's very compact and easily carried. Unlike some of the other products that are bulkier that you'd maybe need to carry in a backpack or in a in a purse. In the case of the Libervant product, it's very easy to carry, you could put it in your wallet, you could put it in a little pocket in a swimming trunks. I’'s also water resistant, so you could actually go swimming with it, and it wouldn't have any degradation as a result of that. The foil pouch is then opened and the patient is able to easily apply it to the inside of the cheek. No water is necessary, as would be the case if it was a pill that needed to be swallowed.

What impressed me is the usability of the product, the fact that it's very reliable in its performance. When I speak about reliability, I'm referring to the fact that there were very few instances where the product didn't perform as required. In the sense that it might have fallen off the chain or off the inside of the cheek happened very rarely. The other aspect of the performance is the ability to deliver diazepam reliably to patients through measurements in the plasma concentrations of diazepam. This was also very reliable in all of the clinical studies that that were done.

Transcript edited for clarity.

REFERENCES
1. Fitch, J. FDA approves diazepam for seizure clusters in patients 2 to 5 years. Contemporary Pediatrics. Accessed April 29, 2024. https://www.contemporarypediatrics.com/view/fda-approves-diazepam-for-seizure-clusters-in-patients-2-to-5-years
2. Aquestive Therapeutics receives US FDA Approval and market access for Libervant (diazepam) buccal film in pediatric patients ages 2 to 5 and provides update on Anaphylm (epinephrine) sublingual film. News release. Aquestive Therapeutics. April 29, 2024. Accessed April 29, 2024. https://finance.yahoo.com/news/aquestive-therapeutics-receives-u-fda-110000681.html