New FDA Approval: Epidiolex

New FDA Approval: Epidiolex

Editor's Note: The following is a guest post written by 2 super-awesome P4 students at the University of Texas College Austin of Pharmacy. I'll let them handle their own bios. Thanks Sammie and Sarah for writing this!

Samantha Le is a P4 student from the University of Texas at Austin College of Pharmacy. Her interests are broad and include ambulatory care, academia, emergency medicine, and pediatric pharmacy. She hopes to complete a PGY1/PGY2 to improve her clinical knowledge and ultimately become board-certified. Lastly, she would love to become a preceptor and mentor future pharmacy students! 

Sarah Piccuirro is a P4 student from UT Austin College of Pharmacy. When Sarah is not studying, you can find her hanging out with her two dogs and eating all the tacos. After switching gears from the social work field, she become interested in the clinical side of pharmacy after her summer hospital IPPE experience. She hopes to obtain a PGY1/PGY2 residency and is interested in specializing in ambulatory care, critical care, or psychiatric pharmacy.

Drug

Epidiolex (cannabidiol extract from cannabis)

Indications

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Epidiolex is indicated for treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome, in patients 2 years of age or older.

(FYI: both of these syndromes are rare and difficult to treat seizure disorders that appear during infancy or childhood).

 

How It Works

The short story is that we don’t really know how it works. There are some theories floating around regarding cannabis receptor mediated GABA/glutamate activity in animal models. But, as we know, animals aren’t people. Well, people are technically animals, but, we digress.

In order to understand how Epidiolex works, we have to differentiate between cannabis and cannabidiol.

Cannabis (CS) is derived from the Cannabis plant, and is what typically comes to mind when we think of marijuana. However, it’s more like a “mother ship”, and is composed of cannabinoids - compounds which act on cannabinoid receptors.

The most well-researched cannabinoids are: tetrahydrocannabinol (THC), cannabidiol, and cannabinol. THC is the main psychoactive component in cannabis, and is primarily responsible for causing feelings of euphoria or feeling “high”.

On the other hand, cannabidiol has low affinity for cannabinoid receptors, and does not cause intoxicating effects like THC.

With that in mind, cannabidiol acts on multiple molecular targets that each play a key role in neuronal excitability. But we need some more studies for a better understanding of the anticonvulsant mechanism of action and treatment targets of cannabidiol.

Notable Adverse Effects

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Epidiolex comes with adverse effects, just like any other drug.

Here are a few worth taking note of:

  • Sleep disturbances
  • Elevated LFTs
  • Diarrhea
  • Infection

The sleep disturbances mentioned above are mostly of the "somnolence, sleepy, lethargy" variety. 

But there are some patients who experienced insomnia, and "poor sleep quality" with Epidiolex.

The main data we have on Epidiolex comes from 3 randomized, double-blind, placebo-controlled trials in a total of 516 patients

These trials looked at either Dravet Syndrome or Lennox-Gastaut Syndrome. In all of them, Epidiolex was combined with other antiepileptic drugs.

It's important to make special note of that. Epidiolex is not to be used as monotherapy at this time. 

That also means that all of the side effects listed above could be due to the combined effect of Epidiolex with other antiepileptic treatments. As an example, valproic acid is notorious for increasing LFTs, and it's a commonly used treatment for both Dravet and Lennox-Gastaut. 

Perhaps now that we have an FDA approval, we'll start to see some research with Epidiolex monotherapy (or at the very least, some real world usage data). That will help us get more info on Epidiolex-specific side effects. 

Epidiolex is also a substrate of CYP3A4 and 2C19. It's recommended to reduce the Epidiolex dose for patients taking moderate/strong inhibitors of either (or to INCREASE the Epidiolex dose for patients taking moderate/strong inducers).  

As a quick aside: thinking about CYP drug interactions sends us into a palm-sweaty panic. You too? Here’s a reminder of some common 3A4 & 2C19 inhibitors:

Current Place in Therapy

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So where does Epidiolex fit?

Before we talk about Epidiolex’s current place in therapy, we have to touch upon the fact that Epidiolex is derived from cannabis (a Class I Controlled Substance).

As a matter of fact, all chemicals derived from the cannabis plant are Class I Controlled Substances. 

Therefore, Epidiolex is a Class I Controlled Substance. 

It’s right up there with heroin, LSD, and methamphetamine.

Depending on what state you live in, being caught with cannabis can land you in jail.

In fact, parents either had to consider moving states or be faced with jail time because they were trying to treat their child’s seizures with marijuana.

And unless you’ve been on Disappointment Island for the past few years, the interest in marijuana legalization has skyrocketed. The medical marijuana industry has been growing (pun intended) since the passing of Proposition 215, or the Compassionate Use Act of 1996.

When we say growing, we mean really, really, growing. In 2017, the legal marijuana market raked in nearly $9 billion dollars in revenue.

What does that mean for Epidiolex?

We'd expect to see some confusion regarding its use and place in treatment. It's an interesting legal tightrope to walk on. When state and federal law don't agree with each other, the rule is to go with whichever is more strict.

That means that any Class I controlled substance has no medicinal use and is therefore illegal. 

But, many states now have legal marijuana dispensaries that are open. And we haven't read any reports of the DEA stepping in and closing them all down.

Does that mean the DEA is thinking about reclassifying cannabis? It's hard to say. Just 2 years ago, they took a vote and decided NOT to reclassify cannabis.  

Epidiolex doesn't have the compound (THC) that causes psychoactive effects and abuse liability, so that may help its cause.

But we also thought that loperamide had nipped the whole "abuse potential" thing in the bud, and we see where that's gotten us

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Another potential barrier is cost. While GW Pharmaceuticals has not yet released a price for Epidiolex, Wall Street analysts predict that it could cost a patient over $30,000 a year.

Surprisingly, this is comparable to the cost of cannabidiol oil purchased at a dispensary which we estimated at around $26,000 a year at appropriate doses.

So Epidiolex is slightly more expensive, but since it's an FDA approved drug it may be covered by insurance. That also means that this exact product has been studied in clinical trials and is subject to good manufacturing practices. You potentially have no idea what you're getting from your local dispensary. 

Controversy aside, these two seizure disorders need better treatment options. Children with Lennox-Gastaut syndrome develop learning problems, delayed motor functions, and worsening prognosis over time.

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Children with Dravet syndrome are at risk of sudden unexplained death.

Current seizure pharmacotherapy recommends valproate or clobazam as first-line agents, followed by topiramate as a second-line agent.

For you avid carb counters, the ketogenic diet also has been looked at for epilepsy with decent results.

However, as you probably know, these medications can have some pretty serious side effects.

Just to list a few...

  • Clobazam has a black box warning for Steven Johnson’s Syndrome (which is great if you like the idea of your skin blistering and falling off)
  • Valproate can cause premature growth ossification in children. Not to mention the whole liver toxicity thing
  • Topiramate may cause cognitive slowing and even suicidal ideations 

Aren't there other treatment options? Not a lot. In fact gabapentin, carbamazepine and oxcarbazepine have actually been shown to worsen seizures for Dravet and Lennox-Gastaut. 

We've always dealt with these drugs and their potential side effects, because that's all that we had. But you can say we're jazzed by the prospect of treatment advancements here.

Conclusion

Epidiolex shows promise for 2 pretty rare seizure disorders. But an FDA approval will likely open the clinical research gates to more therapeutic arenas. 

Even before getting approved, the FDA authorized access to Epidiolex for over 1100 treatment-resistant epilepsy patients through an Expanded Access Program. This is the largest Compassionate Use Program within epilepsy, so there's definitely some promise with the drug. 

And the best thing of all about Epidiolex?

It’s strawberry-flavored.

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