The Rise of Intranasal Treatments in Epilepsy

Andrew N. Wilner, MD

Disclosures

July 11, 2019

The use of nasal sprays for the treatment of epilepsy has gained considerable attention lately. At this past May's American Academy of Neurology (AAN) meeting, Washington University epileptologist R. Edward Hogan, MD, presented two posters outlining the use of diazepam nasal spray.[1,2] This was followed a few weeks later by the US Food and Drug Administration (FDA) approving midazolam nasal spray (Nayzilam) for the treatment of acute repetitive seizures distinct from a patient's usual seizure pattern.

Medscape contributor Andrew Wilner, MD, spoke with Hogan about how the field came to embrace nasal spray solutions for epilepsy and what may change in the wake of recent data and FDA approval.

The Rationale for Intranasal Treatments

With the recent FDA approval of midazolam, can you give us the background on this treatment and how it's going to help our patients?

In the big picture, we're lucky to have a number of antiepileptic medications that are effective. Despite that, probably 20%-30% of patients continue to have seizures, no matter what medicines we give them.

Typically, we've given medications at a specified time of the day, every day. The idea is that that background medication will control the seizures. However, the difficulties arise when those don't work. We know that after you've tried two or three antiepileptic medications, the chances of another long-term medicine helping really go down. The other thing that happens is that when you move to that second or third medication, the side effects tend to go up quite a bit.

So the idea behind these new treatments is not that they're given every day, but they're something we can give when there is an occasion that people need more medications. It has been well established that some people tend to have seizures in clusters, where, if they only have one seizure, then it's very likely that they'll have another one within a few hours. The concept of being able to give an additional medication when there's a pattern to the seizures has been out there for quite some time.

For almost 30 years now, we have had an approved treatment for these kinds of seizures, which is rectal diazepam. Although that is an effective medication, it's not ideal—obviously, especially in an adult population. So the idea has really been to find dosage forms of medications that we can administer quickly and reliably, and that can be used in this seizure pattern, where people can take an extra dose of medicine.

Several medicines have been tried for this over the years, but some of the ones that have really been on the forefront have been intranasal midazolam, which was just approved, and then I did some trials with intranasal diazepam, which is also an effective agent, potentially.

We're really using agents that we know well. Midazolam and diazepam, which is Valium, are well-known molecules, but we want to introduce them intranasally, which is not the usual route. The nose is highly vascular, so the nasal mucosa has the potential to absorb a medication rapidly. Is that the concept?

That's exactly right—that it's easy to give and reliably absorbed. People can try to put a pill in and have it dissolve in their mouth, or there are other ways to try to get a medication in, but to do it reliably in a way that you can count on the medicine getting in relatively quickly is ideal. The nasal route makes that possible.

Recent Evidence on Intranasal Diazepam

Tell us a little about your research. What was the essence of your posters at AAN?

There were two trials that we presented as posters at the AAN. One was an equivalency study looking at people either during a seizure or very shortly afterwards, and comparing that to a time when they had been seizure-free in a relative interictal period.[1] What happened is, patients came in and received two doses of intranasal diazepam, both in this ictal/peri-ictal period and then also in the interictal period. There were very careful comparisons looking at pharmacokinetic curves between those two times. Theoretically, there could be differences between those periods, with autonomic changes or other things that might happen with absorption of the medication. But what comparing those two dosages showed was that they are very much equivalent pharmacokinetically, with no statistical differences, and overall the medicine was well tolerated.

In the second study,[2] we looked at long-term (over 12 months) clinical use in an open-label trial. We gave the medication to patients who we felt had patterns of seizures it would be helpful for, who experience frequent breakthrough seizures or acute repetitive seizures. Long story short, it was well tolerated, with 92% of people who took a single dose feeling that it was helpful and didn't repeat it.

This was kind of the other big news at the AAN. I think it's going to be a well-tolerated and helpful medication.

It sounds like there's a better than 50-50 chance that in addition to midazolam nasal spray, there may be a diazepam product sometime in the near future, so we would have a choice.

Correct.

Identifying Patients Who Will Benefit

Based on your description, it sounds a lot like the treatment of asthma. We give asthma medications that are long-term daily medicines, but then when there's an exacerbation, there are inhalers and sprays to try to tone it down. It might be that these become routine.

Now, when I think of acute repetitive seizures, I'm usually thinking of children. Is this also for adults?

Yes, children and adults. I think the trick with this is to find those patients where they have a pattern. They have a certain seizure type that you think there's a reasonable probability that this is going to recur within a certain amount of time. My practice is in adults, so I've used these medications in adult patients and found them to be very effective.

I'm going to push the discussion a little bit, because for me there's been kind of a slippery slope between acute repetitive seizures and status epilepticus. It doesn't seem difficult to envision somebody calling emergency medical services, and rather than, for example, them jabbing an injection into the bone marrow, maybe a squirt up the nose ought to be step one. Has anybody talked about that?

With all of these things, it has to be used with judgement. Of course, even though seizures aren't completely predictable, we certainly can see patterns with patients. What's really important with this is to say, there's a time where people go into a run of seizures and they're not going to come out, which would be status epilepticus, as you mentioned. I don't think any of these intranasal products are going to be what you want to use for that, if someone is really in an acute exacerbation of seizures. That is unpredictable and uncontrolled, and I think that isn't the overall goal for these.

However, in more predictable seizures, and especially if they have the patterns, then it can be used. That comes down to patient education and understanding that there are different degrees of acuity, of how you would treat a run of seizures. Again, the pattern is what makes the difference. If someone has a typical pattern with it, then fortunately that gives us a leg up in epilepsy, as you well know. But you also have to be very careful to talk to patients about whether something is outside of their usual pattern, or a very prolonged seizure, because that's another route of treatment.

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